Novel polymorphic forms of 3-(1--6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride salt and processes of manufacturing thereof

ABSTRACT

The present invention relates to 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride solvates and crystalline modifications thereof. The present invention further relates to processes of manufacturing these crystalline modifications as well as their use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, which are caused, mediated and/or propagated by the inhibition, regulation and/or modulation of signal transduction of kinases, in particular by the inhibition of tyrosine kinases, e.g. pathophysiological conditions such as cancer.

TECHNICAL FIELD

The present invention relates to3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride, its solvates and crystalline modifications thereof aswell as their medical uses and processes of manufacturing.

PRIOR ART

3-(1-{3-[5-(1-methyl-pipendin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(I)

was first described in international patent applicationsPCT/EP20081003473, filed on 29 Apr. 2008, and PCT/EP2008/005508, filedon 4 Jul. 2008.

In PCT/EP2008/0034733-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileis referred to as compound “A257”. Example 40 of PCT/EP2008/003473describes a first way of synthesizing3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile.Hemisulfate, citrate, tartrate, sulfate, succinate and hydrochloride arementioned as possible salt forms. Besides, example 43 ofPCT/EP2008/003473 describes an alternative way of synthesizing3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile.Example 3 of PCT/EP2008/005508 describes the same first way ofsynthesizing3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileand also mentions hemisulfate, citrate, tartrate, sulfate, succinate andhydrochloride as possible salt forms. Example 4 of PCT/EP20081/005508refers to hydrochloride monohydrate (compound “A7”), hydrobromide,mesylate, besylate, malate, fumurate, maleate and p-tosylate salt forms.However, compound “A7” described in example 4 is not any monohydrate ormonohydrate mixture, but exclusively crystalline modification H2 of3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate (please refer to Example 12 described herein).

Both prior art documents are silent about3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride solvate forms other than monohydrate crystallinemodification H2.

Certain crystalline, i.e. morphological or polymorphic forms ofpharmaceutical compounds may be of interest to those involved in thedevelopment of suitable pharmaceutical dosage forms. This is because ifa certain polymorphic form is not held constant during clinical andstability studies, the exact dosage used or measured may not becomparable from one batch to the other. Once a pharmaceutical compoundis produced for use, it is important to verify the morphological orpolymorphic form delivered in each dosage form to assure that theproduction process delivers the same form and that the same amount ofdrug is included in each dosage. Therefore, it is imperative to assurethat either a single morphological or polymorphic form or a knowncombination of morphological or polymorphic forms is present. Inaddition, certain morphological or polymorphic forms may exhibitenhanced thermodynamic stability and may be more suitable than othermorphological or polymorphic forms for inclusion in pharmaceuticalformulations.

The citation of any reference in this application is not an admissionthat the reference is relevant prior art to this application.

DESCRIPTION OF THE INVENTION

The present invention has the object to provide novel solvate forms of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride as well as novel polymorphic forms thereof.

The object of the present invention has surprisingly been solved in oneaspect by providing3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride solvate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate crystalline modification H2.

In another aspect, the object of the present invention has surprisinglybeen solved by providing3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride solvate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

It has been found that3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride is able to form solvates in crystalline modifications.Examples of such solvates include solvates from water, solvates fromalcohols such as methanol, ethanol, propan-1-ol or propan-2-ol; solvatesfrom organic esters such as ethyl acetate; solvates from nitriles suchas acetonitrile; solvates from ketones such as acetone and butanone;solvates from ethers such as tetrahydrofuran (THF) and solvates fromchlorinated hydrocarbons such as chloroform and solvates of hydrocarbonssuch as n-heptane or toluene. Preferred solvates are formed with polarsolvents, preferably water, alcohols, organic esters, nitriles, ketonesand ethers.

Preferably,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride forms anhydrates and solvates with water, acetone,tetrahydrofuran, methanol, ethyl acetate or n-heptane in crystallinemodifications that means the bound solvent together with3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride build the crystal structure. The molar ratio of thesolvent to3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride could vary as known to skilled persons in the art.Preferably, the molar ratio is between 0.25:1 to 2.5:1, more preferablybetween 0.5:1 to 1:1, most preferably 1:1 (n-heptane solvate 1/15:1). Itshould be understood that the present anhydrates and solvates of theinvention may contain unbound water that is to say water which is otherthan water of crystallization.

Further, the molar ratio of hydrochloride to3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) within3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride can vary for each and all the herein disclosed solvates,anhydrates, hydrates, monohydrates etc. and their crystallinemodifications as known to skilled person in the art. Preferably, themolar ratio is between 0, 5:1 to 1, 5:1, more preferably between 0, 8:1to 1, 2:1, most preferably 1:1.

Hence, in a preferred embodiment,3-(1-{3-[5-(1-methyl-pipendin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride solvate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate crystalline modification H2 is provided in itscrystalline modifications.

Hence, in a further preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride solvate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate is provided in its crystalline modifications.

The object of the present invention has surprisingly been solved inanother aspect by providing3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate is provided in its crystalline modification A1,which is characterized by XRD peaks comprising 4.4°, 15.9° and 22.7° (in°2θ using Cu—Kα₁ radiation, ±0.1°).

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate is provided in its crystalline modification A1,which is characterized by the following XRD data:

Form A1: °2θ (Cu-Kα₁ radiation) Peak No. d/Å ±0.1° 1 20.08 4.4 2 8.5510.3 3 7.43 11.9 4 5.70 15.5 5 5.56 15.9 6 4.99 17.8 7 4.86 18.2 8 4.7418.7 9 4.55 19.5 10 4.46 19.9 11 4.27 20.8 12 4.10 21.6 13 3.91 22.7 143.82 23.3 15 3.65 24.3

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate is provided in its crystalline modification NF6,which is characterized by XRD peaks comprising 16.8°, 18.2° and 25.8°(in °2θ using Cu—Kα, radiation, ±0.1°).

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate is provided in its crystalline modification NF6,which is characterized by the following XRD data:

Form NF6: °2θ (Cu-Kα₁ radiation) Peak No. d/Å ±0.1° 1 17.66 5.0 2 11.078.0 3 10.53 8.4 4 9.35 9.4 5 8.77 10.1 6 6.55 13.5 7 5.83 15.2 8 5.2616.8 9 4.88 18.2 10 4.54 19.5 11 4.48 19.8 12 4.38 20.3 13 4.06 21.9 143.66 24.3 15 3.50 25.4 16 3.45 25.8 17 3.32 26.8 18 3.27 27.2 19 3.2127.8 20 3.12 28.6

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate is provided in its crystalline modification NF4,which is characterized by XRD peaks comprising 6.0°, 15.7° and 24.7° (in°2θ using Cu—Kα₁ radiation, ±0.1°).

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate is provided in its crystalline modification NF4,which is characterized by the following XRD data:

Form NF4: °2θ (Cu-Kα₁ radiation) Peak No. d/Å ±0.1° 1 14.61 6.0 2 8.929.9 3 6.45 13.7 4 6.29 14.1 5 5.63 15.7 6 5.53 16.0 7 5.26 16.8 8 4.8618.2 9 4.19 21.2 10 4.11 21.6 11 4.04 22.0 12 3.94 22.6 13 3.89 22.8 143.76 23.6 15 3.60 24.7 16 3.56 25.0 17 3.49 25.5 18 3.37 26.5 19 3.3226.8 20 3.22 27.7

The object of the present invention has surprisingly been solved inanother aspect by providing3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate crystalline modification H2.

The object of the present invention has surprisingly been solved inanother aspect by providing3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is provided in its crystalline modification H1,which is characterized by XRD peaks comprising 5.9°, 16.0° and 23.4° (in°2θ using Cu—Kα₁ radiation, ±0.1*).

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is provided in its crystalline modification H1,which is characterized by the following XRD data:

Form H1: °2θ (Cu-Kα₁ radiation) Peak No. d/Å ±0.1° 1 14.88 5.9 2 9.998.8 3 7.83 11.3 4 7.25 12.2 5 6.10 14.5 6 5.84 15.2 7 5.52 16.0 8 5.3816.5 9 4.92 18.0 10 4.12 21.6 11 3.80 23.4 12 3.57 24.9 13 3.49 25.5 143.30 27.0 15 2.95 30.3

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is provided in its crystalline modification NF3,which is characterized by XRD peaks comprising 9.9°, 15.7° and 24.1° (in°2θ using Cu—Kα₁ radiation, ±0.1°).

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is provided in its crystalline modification NF3,which is characterized by the following XRD data:

Form NF3: °2θ (Cu-Kα₁ radiation) Peak No. d/Å ±0.1° 1 14.83 6.0 2 8.969.9 3 6.92 12.8 4 5.62 15.7 5 5.44 16.3 6 5.26 16.9 7 4.38 20.3 8 4.3220.6 9 3.79 23.5 10 3.69 24.1 11 3.59 24.8 12 3.55 25.1 13 3.45 25.8 143.35 26.6 15 3.22 27.7

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is provided in its crystalline modification NF2,which is characterized by XRD peaks comprising 5.2°, 23.8° and 24.5° (in°2θ using Cu—Kα₁ radiation, ±0.1°).

In a preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is provided in its crystalline modification NF2,which is characterized by the following XRD data:

Form NF2: °2θ (Cu-Kα₁ radiation) Peak No. d/Å ±0.1° 1 16.84 5.2 2 8.4110.5 3 8.14 10.9 4 5.70 15.5 5 5.59 15.8 6 4.87 18.2 7 4.19 21.2 8 4.0022.2 9 3.91 22.7 10 3.78 23.5 11 3.73 23.8 12 3.63 24.5 13 3.52 25.3 143.49 25.5 15 3.36 26.5 16 3.33 26.7 17 3.23 27.6 18 3.19 28.0 19 3.1528.3 20 3.12 28.6

In a further preferred embodiment,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate is provided in its crystalline modificationH2, which is characterized by the following XRD data:

Form H2: °2θ (Cu-Kα₁ radiation) Peak No. d/Å ±0.1° (h, k, l) 1 8.71 10.1(1, 0, 0) 2 8.22 10.8 (−1, 1, 1) 3 7.59 11.6 (1, 2, 0) 4 6.78 13.0 (0,3, 1) 5 6.58 13.5 (−1, 3, 1) 6 5.73 15.4 (−1, 4, 1) 7 4.98 17.8 (−1, 1,2) 8 4.84 18.3 (−2, 1, 1) 9 4.68 19.0 (−2, 2, 1) 10 4.43 20.0 (−2, 3, 1)11 4.35 20.4 (2, 0, 0) 12 3.73 23.9 (−2, 4, 2) 13 3.64 24.5 (0, 5, 2) 143.39 26.3 (0, 6, 2) 15 3.13 28.5 (−3, 2, 2)

In the course of the present invention, the term “crystallinemodification” is used as a synonym for terms “crystalline form”,“polymorphic form”, “polymorphic modification”, “morphological form” andthe like.

The crystalline modifications of the present invention, in particularcrystalline modification A1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate, crystalline modification NF6 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate, crystalline modification NF4 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate, crystalline modification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate, crystalline modification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate, crystalline modification NF2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate, and crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate, are surprisingly characterized by, amongothers, a reduced hygroscopicity, a better compressibility during thetableting process, a prolonged shelf life, a better thermodynamicstability, i.e. stability against heat and humidity, a better resistanceto sunlight, i.e. UV-light, an increased bulk density, an improvedsolubility, bioavailability characteristics which are constant from onebatch to the other, better flow and handling properties in the tabletingprocess, an improved colour stability and better filtration propertiesin the production process. Therefore, by use of the crystallinemodifications of the present invention, it is possible to obtainpharmaceutical formulations with improved homogeneity, stability, purityand uniformity from one batch to the other.

Furthermore, crystalline modification A1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate shows superior properties for drying purposes(no loss of hydrate water can occur) as well as significantly increasedsolubility in USP Simulated Gastric Juice compared to thethermodynamically stable crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

Crystalline modification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate shows significantly increased solubility in 0.1NHCl (pH 1.0) compared to the thermodynamically stable crystallinemodification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

On the other hand, crystalline modification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate shows significantly increased solubility in 0.1 NHCl (pH 1.0) compared to the thermodynamically stable crystallinemodification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

In contrast, crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate represents the thermodynamically stablehydrate form and shows superior properties in terms of hygroscopicitybehavior compared to3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate crystalline modifications H1 and NF3, as well asto3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate crystalline modification A1, namely physicalstability of the crystal form throughout the entire RH range 0-98% withvery small water uptake levels.

The crystalline modifications of the present invention can becharacterized according to standard methods which can be found e.g. inRolf Hilfiker, ‘Polymorphism in the Pharmaceutical Industry’, Wiley-VCH,Weinheim 2006, and references therein, e.g. X-Ray diffraction (XRD;chapter 6), IR and Raman spectroscopy (chapter 5), Differential ScanningCalorimetry (DSC) and Thermogravimetric Analysis (TGA) (chapter 3),Water Vapour Sorption Studies (chapter 9), or which can be found e.g. inH.G. Brittain (editor), Polymorphism in Pharmaceutical Solids, Vol. 95,Marcel Dekker Inc., New York 1999 (chapter 6: all there mentionedtechniques).

3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride solvate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate crystalline modification H2,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride solvate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride solvate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate crystalline modification H2 in its crystallinemodifications,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride solvate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate in its crystalline modifications,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate excluding3-(1-{3-[5-(1-methyl-pipendin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate crystalline modification H2,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification A1,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification NF6,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification NF4,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in its crystalline modification H1,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in its crystalline modification NF3,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in its crystalline modification NF2, and3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate in its crystalline modification H2 arehereinafter referred to as “product(s) of the (present) invention”.

3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) can be synthesized as described in PCT/EP2008/003473,example 40, and PCT/EP2008/005508, example 3, as follows:

To a suspension of 13.0 g (56.5 mmol) of3-(5-hydroxy-pyrimidin-2-yl)-benzoic acid methylester and 13.4 g (62.1mmol) of N-Boc-piperidinemethanol in 115 ml THF 17.7 g (67.8 mmol) oftriphenyl-phosphine are given. The suspension is cooled down to 5° C. Tothe suspension kept at this temperature 13.3 ml (67.8 mmol) ofdiisopropylazodicarboxylate are given dropwise under stirring within 45minutes. The reaction mixture is stirred at room temperature for onehour. Subsequently, further 22.2 g (84.7 mmol) of triphenylphosphine and16.6 ml (84.7 mmol) of diisopropylazodicarboxylate are added. Thereaction mixture is stirred at room temperature for 18 hours andconcentrated in vacuo. The resulting solid of4-[2-(3-methoxycarbonyl-phenyl)-pyrimidin-5-yloxymethyl]-piperidine-1-carbonicacid tert.-butylester is sucked off, washed with diethylether andsubjected to chromatography (silica gel column anddichloromethan/methanol as eluent/mobile phase).

To a suspension of 1.71 g (3.99 mmol) of4-[2-(3-methoxycarbonyl-phenyl)-pyrimidin-5-yloxymethyl]-piperidine-1-carbonicacid tert.-butylester in 20 ml THF 25 ml (25 mmol) of a 1 M solution ofdiisobutylaluminiumhydride in THF are given dropwise under nitrogen. Thereaction mixture is stirred for one hour at room temperature and mixedwith a saturated solution of sodium sulfate. The resulting precipitateis sucked off and washed with THF and hot 2-propanol. The filtrate isconcentrated and re-crystallized from tert.-butylmethylether, resultingin{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-phenyl}-methanolas beige crystals.

To a solution of 313 mg (1.00 mmol) of{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-phenyl}-methanolin 2 ml THF 264 mg (1.30 mmol) of3-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile and 397 mg (1.5 mmol)triphenylphosphine are added subsequently. The reaction mixture iscooled in an ice bath and 294 μl (1.5 mmol) ofdiisopropylazodicarboxylate are added dropwise. The reaction mixture isstirred at room temperature for 18 hours and then concentrated. Theresidue is subjected to chromatography (silica gel column anddichloromethan/methanol as eluent/mobile phase). The product containingfractions are pooled, concentrated and the residue of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileis decocted with tert.-butylmethylether, sucked off and dried in vacuo.

Alternatively,3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) can be synthesized as described in PCT/EP2008/003473,example 43, as follows:

To a suspension of 4.15 g (20 mmol) of3-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in 40 ml of1-methyl-2-pyrrolidon 6.00 g (21 mmol) of5-bromo-2-(3-chloromethyl-phenyl)-pyrimidine and 2.76 g (341 mmol) ofpotassiumcarbonate are given. The reaction mixture is stirred at 80° C.for 18 hours. Subsequently, the reaction mixture is given onto 200 mlwater. The resulting precipitate of3-{1-[3-(5-bromopyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrileis sucked off, washed with water and dried in vacuo.

To a solution of solution of 18.0 g (41.0 mmol) of3-{1-[3-(5-bromopyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrilein 85 ml DMF 11.8 g (47 mmol) of bis(pinacolato)diboron and 11.9 g (122mmol) of potassium acetate are given. The reaction mixture is heated upto 80° C. under nitrogen. After 15 minutes of stirring at thistemperature 273 mg (1.22 mmol) of palladium(II)-acetate are added andthe reaction mixture is stirred for 2 hours at 80° C. under nitrogen.Subsequently, the reaction mixture is allowed to cool down to roomtemperature before the addition of water and dichloromethane, filtrationover diatomite/kieselguhr and separation of the organic phase.

The organic phase is dried over sodium sulphate and concentratedyielding3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-benzyl}-1,6-dihydro-pyridazin-3-yl)-benzonitrileas grey solid, which can be used for subsequent reactions withoutpurification.

To a suspension of 5.33 g (10.9 mmol) of3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-benzyl}-1,6-dihydro-pyridazin-3-yl)-benzonitrilein 35 ml THF and 35 ml water 4.93 g (49.4 mmol) of sodiumperborate aregiven in portions under ice cooling before it is stirred at roomtemperature for 2 hours. The reaction mixture is mixed with 300 ml ofdichloromethan and 100 ml of saturated ammoniumchloride solution. Theorganic phase is separated, dried over sodium sulphate and concentrated.The residue of3-{1-[3-(5-hydroxy-pyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrileis re-crystallized from methanol.

To a suspension of 25 g (65.6 mmol) of3-{1-[3-(5-hydroxy-pyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrilein 250 ml THF 15.6 g (68.8 mmol) of N-Boc-4-piperidine-methanol and 19.1g (72.1 mmol) of triphenylphosphine are subsequently added. Then, 14.9ml (72.1 mmol) of diisopropylazodicarboxylate are added dropwise underice cooling. The resulting solution is stirred at room temperature for 2hours. The reaction mixture is further mixed with 750 ml of 2-propanoland 13.1 ml of a 0.5 M solution of potassiumhydroxid in ethanol. Theresulting precipitate of4-(2-{3-[3-(3-cyano-phenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}-pyrimidin-5-yloxymethyl)-piperidine-1-carbonicacid tert.-butylester is sucked off, washed with diethylether and driedin vacuo.

To a solution of 16.0 g (28.0 mmol) of4-(2-{3-[3-(3-cyano-phenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}-pyrimidin-5-yloxymethyl)-piperidine-1-carbonicacid tert.-butylester in 80 ml formic acid 6.60 ml of 35% aqueousformaldehyde solution are given. The reaction mixture is stirred at atemperature of 110° C. for 2 hours before 300 ml water are added. Thereaction mixture is concentrated in vacuo to a volume of 150 ml and isthen extracted with 200 ml of dichloromethane. The organic phase iswashed with sodiumbicarbonate solution, dried over sodium sulphate andconcentrated. The residue of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileis re-crystallized from 2-propanol.

In another aspect of the invention, a pharmaceutical compositioncomprising a therapeutically effective amount of at least one product ofthe invention is provided.

In a preferred embodiment, the pharmaceutical composition furthercomprises at least one additional compound selected from the groupconsisting of physiologically acceptable excipients, auxiliaries,adjuvants, diluents, carriers and/or additional pharmaceutically activesubstances other than the products of the invention.

A further embodiment of the present invention is a process for themanufacture of said pharmaceutical compositions, characterized in thatone or more products of the invention and one or more compounds selectedfrom the group consisting of solid, liquid or semiliquid excipients,auxiliaries, adjuvants, diluents, carriers and pharmaceutically activesubstances other than the products of the invention, are converted in asuitable dosage form.

As used herein, the term “effective amount” refers to any amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician.

Furthermore, the term “therapeutically effective amount” means anyamount which, as compared to a corresponding subject who has notreceived such amount, results in improved treatment, healing,prevention, or amelioration of a disease, disorder, or side effect, or adecrease in the rate of advancement of a disease or disorder. The termalso includes within its scope amounts effective to enhance normalphysiological function.

In another aspect of the invention, a medicament comprising at least oneproduct of the invention or a pharmaceutical composition as describedherein is provided.

In a further aspect of the invention, a medicament as described hereinfor use in the treatment and/or prophylaxis of physiological and/orpathophysiological conditions, which are caused, mediated and/orpropagated by the inhibition, regulation and/or modulation of signaltransduction of kinases, in particular by the inhibition of tyrosinekinases, preferably Met-kinase, is provided. A corresponding use for thepreparation of a medicament for the treatment and/or prophylaxis of theaforementioned conditions is intended to be comprised.

In a further aspect of the invention, a medicament as described hereinfor use in the treatment and/or prophylaxis of physiological and/orpathophysiological conditions selected from the group consisting of:“cancer, tumour, malignant tumours, benign tumours, solid tumours,sarcomas, carcinomas, hyperproliferative disorders, carcinoids, Ewingsarcomas, Kaposi sarcomas, brain tumours, tumours originating from thebrain and/or the nervous system and/or the meninges, gliomas,glioblastomas, neuroblastomas, stomach cancer, kidney cancer, kidneycell carcinomas, prostate cancer, prostate carcinomas, connective tissuetumours, soft tissue sarcomas, pancreas tumours, liver tumours, headtumours, neck tumours, laryngeal cancer, oesophageal cancer, thyroidcancer, osteosarcomas, retinoblastomas, thymoma, testicular cancer, lungcancer, lung adenocarcinoma, small cell lung carcinoma, bronchialcarcinomas, breast cancer, mamma carcinomas, intestinal cancer,colorectal tumours, colon carcinomas, rectum carcinomas, gynaecologicaltumours, ovary tumours/ovarian tumours, uterine cancer, cervical cancer,cervix carcinomas, cancer of body of uterus, corpus carcinomas,endometrial carcinomas, urinary bladder cancer, urogenital tract cancer,bladder cancer, skin cancer, epithelial tumours, squamous epithelialcarcinoma, basaliomas, spinaliomas, melanomas, intraocular melanomas,leukaemias, monocyte leukaemia, chronic leukaemias, chronic myeloticleukaemia, chronic lymphatic leukemia, acute leukaemias, acute myeloticleukaemia, acute lymphatic leukaemia and/or lymphomas” is provided. Acorresponding use for the preparation of a medicament for the treatmentand/or prophylaxis of the aforementioned conditions is intended to becomprised.

In another aspect of the invention, a medicament as described herein isprovided, wherein in such medicament comprises at least one additionalpharmacologically active substance (drug, ingredient).

In a preferred embodiment the at least one pharmacologically activesubstance is a substance as described herein.

In another aspect of the invention, a medicament as described herein isprovided, wherein the medicament is applied before and/or during and/orafter treatment with at least one additional pharmacologically activesubstance.

In a preferred embodiment the at least one pharmacologically activesubstance is a substance as described herein.

In a further aspect of the invention, a kit comprising a therapeuticallyeffective amount of at least one product of the invention and/or atleast one pharmaceutical composition as described herein and atherapeutically effective amount of at least one furtherpharmacologically active substance other than the products of theinvention is provided.

Products of the invention may be used in combination with one or moreother pharmacologically active substances (ingredients, drugs) in thetreatment, prevention, suppression or amelioration of diseases orconditions for which products of the invention or the other substanceshave utility. Typically the combination of the drugs is safer or moreeffective than either drug alone, or the combination is safer or moreeffective than would it be expected based on the additive properties ofthe individual drugs. Such other drug(s) may be administered, by a routeand in an amount commonly used contemporaneously or sequentially with aproduct of the invention. When a product of the invention is usedcontemporaneously with one or more other drugs, a combination productcontaining such other drug(s) and the product of the invention ispreferred. However, combination therapy also includes therapies in whichthe product of the invention and one or more other drugs areadministered on different overlapping schedules. It is contemplated thatwhen used in combination with other active ingredients, the product ofthe present invention or the other active ingredient or both may be usedeffectively in lower doses than when each is used alone. Accordingly,the pharmaceutical compositions of the present invention (pharmaceuticalcompositions as described herein) include those that contain one or moreother active ingredients, in addition to a product of the invention.

Examples of other pharmacologically active substances (ingredients,drugs) that may be administered in combination with a product of theinvention, and either administered separately or in the samepharmaceutical composition, include, but are not limited to thecompounds classes and specific compounds listed in Table 1:

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfaneProcarbazine Ifosfamide Altretamine Melphalane EstramustinphosphateHexamethylmelamine Mechlorethamine Thiotepa Streptozocine ChlorambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(AeternaZentaris) Carboxyphthalatoplatinum Satraplatin (Johnson Matthey)Tetraplatin BBR-3464 (Hoffrnann-La Ormiplatin Roche) Iproplatin SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycine 5-FluoruracilFludarabine Floxuridine Pentostatine 2-Chlordesoxyadenosine Raltitrexede6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-Fluordesoxycytidine Irofulven(MGI Pharma) Methotrexate DMDC (Hoffmann-La Roche) IdatrexateEthinylcytidine (Taiho) Topoisomerase Amsacrine Rubitecane (SuperGen)inhibitors Epirubicine Exatecanmesylate (Daiichi) Etoposide Quinamed(ChemGenex) Teniposide or Mitoxantrone Gimatecane (Sigma-Tau)Irinotecane (CPT-11) Diflomotecane (Beaufour- 7-Ethyl-10- Ipsen)hydroxycamptothecine TAS-103 (Taiho) Topotecane Elsamitrucine (Spectrum)Dexrazoxanet (TopoTarget) J-107088 (Merck & Co) Pixantrone(Novuspharrna) BNP-1350 (BioNumerik) Rebeccamycin-Analogue CKD-602(Chong Kun Dang) (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576(Novuspharrna) Antitumor antibiotics Dactinomycin (Actinomycin AmonafideD) Azonafide Doxorubicin (Adriamycin) Anthrapyrazole DeoxyrubicinOxantrazole Valrubicin Losoxantrone Daunorubicin (Daunomycin)Bleomycinsulfate (Blenoxan) Epirubicin Bleomycinacid TherarubicinBleomycin A Idarubicin Bleomycin B Rubidazone Mitomycin C PlicamycinpMEN-10755 (Menarini) Porfiromycin GPX-100 (GemCyanomorpholinodoxorubicin Pharmaceuticals) Mitoxantron (Novantron)Antimitotic agents Paclitaxel SB 408075 (Glaxo Docetaxel SmithKline)Colchicin E7010 (Abbott) Vinblastine PG-TXL (Cell Therapeutics)Vincristine IDN 5109 (Bayer) Vinorelbine A 105972 (Abbott) Vindesine A204197 (Abbott) Dolastatine 10 (NCI) LU 223651 (BASF) Rhizoxine(Fujisawa) D 24851 (ASTA Medica) Mivobuline (Warner-Lambert) ER-86526(Eisai) Cemadotine (BASF) Combretastatine A4 (BMS) RPR 109881A (Aventis)Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilon B(Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel(Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly)!DN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient NeuroPharma)Auristatine PE (Teikoku Hormone) Azaepothilon B (BMS) BMS 247550 (BMS)BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-Prodrug (OXiGENE) BMS 188797(BMS) Dolastatin-10 (NrH) Taxoprexine (Protarga) CA-4 (OXiGENE)Aromatase inhibitors Aminoglutethimide Exemestane Letrozole Atamestane(BioMedicines) Anastrazole YM-511 (Yamanouchi) FormestaneThymidylatesynthase Pemetrexed (Eli Lilly) Nolatrexed (Eximias)inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonistsTrabectedine (PharmaMar) Mafosfamide (Baxter International) Glufosfamide(Baxter International) Apaziquone (Spectrum Albumin + 32P (IsotopeSolutions) Pharmaceuticals) Thymectacine (NewBiotics) O6-Benzylguanine(Paligent) Edotreotide (Novartis) Farnesyltransferase Arglabine(NuOncology Labs) Tipifarnibe (Johnson & Johnson) inhibitors Ionafarnibe(Schering- Perillylalcohol (DOR Bio- Plough) Pharma) BAY-43-9006 (Bayer)Pump inhibitors CBT-1 (CBA Pharma) Zosuquidar-TrihydrochlorideTariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG) Biricodar-Dicitrate(Vertex) Histoneacetyltransferase Tacedinaline (Pfizer)Pivaloyloxymethylbutyrate inhibitors SAHA (Aton Pharma) (Titan) MS-275(Schering AG) Depsipeptide (Fujisawa) Metalloproteinase Neovastat(Aeterna CMT-3 (CollaGenex) inhibitors/ Laboratories) BMS-275291(Celltech) Ribonucleosidereduktase Marimastat (British Biotech)Tezacitabine (Aventis) inhibitors Galliummaltolate (Titan) Didox(Molecules for Health) Triapine (Vion) TNF-alpha agonists/ Virulizine(Lorus Therapeutics) Revimide (Celgene) antagonists CDC-394 (Celgene)Endotheline-A receptor Atrasentane (Abbot) YM-598 (Yamanouchi)antagonists ZD-4054 (AstraZeneca) Retinoic acid receptor Fenretinide(Johnson & Alitretinoin (Ligand) agonists Johnson) LGD-1550 (Ligand)Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology)Adenocarzinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Noreline (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccine (CTL 13-Alethine (Dovetail) Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (GemVax) Hormonal and anti-Estrogens Prednisone hormonal agents Conjugated EstrogensMethylprednisolone Ethinylestradiole Prednisolone ChlorotrianisenAminoglutethimide Idenestrole Leuprolide HydroxyprogesteroncaproateGoserelin Medroxyprogesterone Leuporelin Testosterone CetrorelixTestosteronpropionate Bicalutamide Fluoxymesterone FlutamideMethyltestosterone Octreotide Diethylstilbestrole Nilutamide MegestroleMitotane Tamoxifen P-04 (Novogen) Toremofine 2-MethoxyestradiolDexamethasone (EntreMed) Arzoxifen (Eli Lilly) Photodynamic Talaporfine(Light Sciences) Pd-Bacteriopheophorbide agents Theralux(Theratechnologies) (Yeda) Motexafin Gadolinium Lutetium-Texaphyrine(Pharmacyclics) (Pharmacyclics) Hypericine Tyrosinkinase inhibitorsImatinib (Novartis) Kahalid F (PharmaMar) Leflunomid CEP-701 (Cephalon)(Sugen/Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518(Millenium) Erlotinib (Oncogene Science) PKC412 (Novartis) Canertjnib(Pfizer) Phenoxodiol O Squalamin (Genaera) Trastuzumab (Genentech)SU5416 (Pharmacia) C225 (ImClone) SU6668 (Pharmacia) rhu-Mab (Genentech)ZD4190 (AstraZeneca) MDX-H210 (Medarex) ZD6474 (AstraZeneca) 2C4(Genentech) Vatalanib (Novartis) MDX-447 (Medarex) PKI166 (Novartis)ABX-EGF (Abgenix) GW2016 (GlaxoSmithKline) IMC-1C11 (ImClone) EKB-509(Wyeth) EKB-569 (Wyeth) Different agents SR-27897 (CCK-A inhibitor,BCX-1777 (PNP inhibitor, Sanofi-Synthelabo) BioCryst) Tocladesine(cyclic-AMP Ranpirnase (Ribonuclease agonist, Ribapharm) stimulans,Alfacell) Alvocidib (CDK inhibitor, Galarubicin (RNA synthesis Aventis)inhibitor, Dong-A) CV-247 (COX-2-Inhibitor, Ivy Tirapazamin (reducingagent, Medical) SRI International) P54 (COX-2 inhibitor, Phyto-N-Acetylcystein (reducing pharm) agent, Zambon) CapCell ™ (CYP450stimulans, R-Flurbiprofen (NF-kappaB Bavarian Nordic) inhibitor, Encore)GCS-IOO (gal3 antagonist, 3CPA (NF-kappaB inhibitor, GlycoGenesys)Active Biotech) G17DT immunogen (Gastrin Seocalcitol (Vitamin-D receptorinhibitor, Aphton) agonist, Leo) Efaproxiral (Oxygenator, Allos131-I-TM-601 (DNA Therapeutics) antagonist, TransMolecular) PI-88(Heparanase inhibitor, Eflornithin (ODC inhibitor, Progen) ILEXOncology) Tesmilifen (Histamine antagonist, Minodronic acid (OsteoclastsYM BioSciences) inhibitor, Yamanouchi) Histamine (Histamine-H2 Indisulam(p53 stimulans, receptor agonist, Maxim) Eisai) Tiazofurin (IMPDHinhibitor, Aplidin (PPT inhibitor, PharmaMar) Ribapharm) Rituximab (CD20antibody, Cilengitide (Integrine antagonist, Genentech) Merck KGaA)Gemtuzumab (CD33 antibody, SR-31747 (IL-1 antagonist, Wyeth Ayerst)Sanofi-Synthelabo) PG2 (Hematopoesis enhancer, CCI-779 (mTOR kinaseinhibitor, Pharmagenesis) Wyeth) Immunol ™ (Triclosan oral Exisulind(PDE-V inhibitor, irrigation, Endo) Cell Pathways) Triacetyluridine(Uridine pro- CP-461 (PDE-V inhibitor, Cell drug, Wellstat) Pathways)SN-4071 (sarcoma agent, AG-2037 (GART inhibitor, Signature BioScience)Pfizer) TransMID-107 ™ (Immunotoxine, WX-UK1 (Plasminogen activator KSBiomedix) inhibitor, Wilex) PCK-3145 (Apoptosis enhancer, PBI-1402 (PMNstimulans, Procyon) ProMetic LifeSciences) Doranidazole (Apoptosisenhancer, Bortezomib (Proteasome Pola) inhibitor, Millennium) CHS-828(cytotoxic agent, SRL-172 (T-cell stimulans, Leo) SR Pharma)trans-Retinoic acid (Differentiator, TLK-286 (Glutathione-S- NIH)transferase inhibitor, Telik) MX6 (Apoptosis enhancer, PT-100 (Growthfactor agonist, MAXIA) Point Therapeutics) Apomin (Apoptosis enhancer,Midostaurin (PKC inhibitor, ILEX Oncology) Novartis) Urocidine(Apoptosis enhancer, Bryostatin-1 (PKC stimulans, Bioniche) GPC Biotech)Ro-31-7453 (Apoptosis enhancer, CDA-II (Apoptosis enhancer, La Roche)Everlife) Brostallicin (Apoptosis enhancer, SDX-101 (Apoptosis enhancer,Pharmacia) Salmedix) Ceflatonin (Apoptosis enhancer, ChemGenex)

In a preferred embodiment, a product of the invention is administered incombination with one or more known anti-tumor agents, such as thefollowing: estrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxics, antiproliferative agents,prenyl proteintransferase inhibitors, HMG-CoA-reductase inhibitors, HIVprotease inhibitors, reverse transcriptase inhibitors, angiogenesisinhibitors.

The products of the invention are in particular well suited foradministration in combination with radiotherapy. The synergistic effectsof VEGF inhibition in combination with radiotherapy are known to theskilled artisan (WO 00/61186).

The term “estrogen receptor modulators” in the course of the presentinvention refers to compounds that interfere with or inhibit the bindingof estrogen to estrogen receptor—independently from the mode of action.Non-limiting examples of estrogen receptor modulators are tamoxifen,raloxifen, idoxifen, LY353381, LY 117081, toremifen, fulvestrant,4-[7-(2,2-Dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl-2,2-dimethyl-propanoate,4,4′-Dihydroxybenzophenon-2,4-dinitrophenylhydrazone and SH646.

The term “androgen receptor modulators” in the course of the presentinvention refers to compounds that interfere with or inhibit the bindingof androgens to androgen receptor—independently from the mode of action.Non-limiting examples of androgen receptor modulators are finasterideand other 5alpha-reductase inhibitors, nilutamide, flutamide,bicalutamide, liarozole and abirateron acetate.

The term “retinoid receptor modulators” in the course of the presentinvention refers to compounds that interfere with or inhibit the bindingof retinoids to retinoid receptor—independently from the mode of action.Non-limiting examples of retinoid receptor modulators are bexaroten,tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,alpha-difluoromethylomithine, ILX23-7553,trans-N-(4′-Hydroxyphenyl)retinamide and N-4-carboxyphenylretinamide.

The term “cytotoxics” in the course of the present invention refers tocompounds that primarily trigger cell death through direct action oncell function(s) or which interfere with or inhibit cell myosis, such asalkylating agents, tumor necrosis factors, intercalating agents,microtubule inhibitors and topoisomerase inhibitors. Non-limitingexamples of cytotoxics are tirapazimin, sertenef, cachectine,ifosfamide, tasonermine, lonidamine, carboplatin, altretamine,prednimustine, dibromodulcit, ranimustine, fotemustine, nedaplatin,oxaliplatin, temozolomide, heptaplatin, estramustin,improsulfan-tosylate, trofosfamide, nimustine, dibrospidium-chloride,pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-amindichloro(2-methylpyridine)platin, benzylguanine,glufosfamide, GPX100,(trans,trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platin(II)]bis-[diamine(chloro)platin(II)]-tetrachloride,diarizidinyispermine, arsenium trioxide,1-(11-Dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantren, mitoxantron, pirarubicin, pinafide,valrubicine, amrubicine, antineoplaston,3′-desamino-3′-morpholino-13-desoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide, MEN10755 and4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (WO00/50032).

Non-limiting examples of microtubule inhibitors are paclitaxel,vindesine-sulfate, 3′,4′-dideshydro-4′-desoxy-8′-norvincaleukoblastine,docetaxol, rhizoxine, dolastatine, mivobuline-isethionate, auristatine,cemadotine, RPR109881, BMS184476, vinflunine, cryptophycine,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)-benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-Lvalyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797.

Non-limiting examples of topoisomerase inhibitors are topotecane,hycaptamine, irinotecane, rubitecane,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusine,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo-[de]-pyrano-[3′,4′:b,7]indolizino[1,2b]quiinoline-10,13(9H,15H)-dione,lurtotecane, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecine, BNP1350,BNPI1100, BN80915, BN80942, etoposide-phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-desoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylendioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-aminoethyl)amino]-benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]-acridine-6-one,N-[1-[2(diethylamino)ethylamino)]-7-methoxy-9-oxo-9H-thioxane-then-4-ylmethyl]formamide,N-(2-(dimethyl-amino)-ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna.

Non-limiting examples of antiproliferative agents are antisense RNA- andantisense-DNA oligonucleotides, such as G3139, ODN698, RVASKRAS, GEM231and INX3001, as well as antimetabolites such as enocitabine, carmofur,tegafur, pentostatine, doxifluridine, trimetrexate, fludarabine,capecitabine, galocitabine, cytarabinocfosfate, fosteabinesodiumhydrate, raltitrexed, paltitrexide, emitefur, tiazofurine,decitabine, nolatrexed, pemetrexed, nelzarabine,2′-desoxy-2′-methylidencytidine, 2′-fluoromethylen-2′-desoxycytidine,N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-desoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidine, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazine-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutaminicacid, aminopterine, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,1′-diaza-tetracyclo-(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lometrexole, dexrazoxane, methioninase,2′-cyan-2′-desoxy-N4-palmitoyl-1-B-D-arabinofuranosylcytosine and3-aminopyridine-2-carboxaldehyde-thiosemicarbazone.

“Antiproliferative agents” also comprises monoclonal antibodies againstgrowth factors that have not been listed under “angiogenesisinhibitors”, such as trastuzumab, as well as tumor suppressor genes,such as p53.

The pharmaceutical compositions of the present invention (as describedherein) may be administered by any means that achieve their intendedpurpose. For example, administration may be by oral, parenteral,topical, enteral, intravenous, intramuscular, inhalant, nasal,intraarticular, intraspinal, transtracheal, transocular, subcutaneous,intraperitoneal, transdermal, or buccal routes. Alternatively, orconcurrently, administration may be by the oral route. The dosageadministered will be dependent upon the age, health, and weight of therecipient, kind of concurrent treatment, if any, frequency of treatment,and the nature of the effect desired. Parenteral administration ispreferred. Oral administration is especially preferred.

Suitable dosage forms include, but are not limited to capsules, tablets,pellets, dragees, semi-solids, powders, granules, suppositories,ointments, creams, lotions, inhalants, injections, cataplasms, gels,tapes, eye drops, solution, syrups, aerosols, suspension, emulsion,which can be produced according to methods known in the art, for exampleas described below:

tablets: mixing of active ingredient/s and auxiliaries, compression ofsaid mixture into tablets (direct compression), optionally granulationof part of mixture before compression. capsules:

mixing of active ingredient/s and auxiliaries to obtain a flowablepowder, optionally granulating powder, filling powders/granulate intoopened capsules, capping of capsules.

semi-solids (ointments, gels, creams): dissolving/dispersing activeingredient/s in an aqueous or fatty carrier; subsequent mixing ofaqueous/fatty phase with complementary fatty/aqueous phase,homogenization (creams only).

suppositories (rectal and vaginal): dissolving/dispersing activeingredient/s in carrier material liquified by heat (rectal: carriermaterial normally a wax; vaginal: carrier normally a heated solution ofa gelling agent), casting said mixture into suppository forms, annealingand withdrawal suppositories from the forms.

aerosols: dispersing/dissolving active agent/s in a propellant, bottlingsaid mixture into an atomizer.

In general, non-chemical routes for the production of pharmaceuticalcompositions and/or pharmaceutical preparations comprise processingsteps on suitable mechanical means known in the art that transfer one ormore products of the invention into a dosage form suitable foradministration to a patient in need of such a treatment. Usually, thetransfer of one or more products of the invention into such a dosageform comprises the addition of one or more compounds, selected from thegroup consisting of carriers, excipients, auxiliaries and pharmaceuticalactive ingredients other than the products of the invention. Suitableprocessing steps include, but are not limited to combining, milling,mixing, granulating, dissolving, dispersing, homogenizing, castingand/or compressing the respective active and non-active ingredients.Mechanical means for performing said processing steps are known in theart, for example from Ullmann's Encyclopedia of Industrial Chemistry,5th Edition. In this respect, active ingredients are preferably at leastone product of the invention and one or more additional compounds otherthan the products of the invention, which show valuable pharmaceuticalproperties, preferably those pharmaceutical active agents other than theproducts of the invention, which are disclosed herein.

Particularly suitable for oral use are tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal use are suppositories, suitable for parenteral use are solutions,preferably oil-based or aqueous solutions, furthermore suspensions,emulsions or implants, and suitable for topical use are ointments,creams or powders. The products of the invention may also be lyophilisedand the resultant lyophilisates used, for example, for the preparationof injection preparations. The preparations indicated may be sterilisedand/or comprise assistants, such as lubricants, preservatives,stabilisers and/or wetting agents, emulsifiers, salts for modifying theosmotic pressure, buffer substances, dyes, flavours and/or a pluralityof further active ingredients, for example one or more vitamins.

Suitable excipients are organic or inorganic substances, which aresuitable for enteral (for example oral), parenteral or topicaladministration and do not react with the products of the invention, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, suchas lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheatstarch, rice starch, potato starch), cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, magnesium stearate, talc, gelatine, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,polyvinyl pyrrolidone and/or vaseline.

If desired, disintegrating agents may be added such as theabove-mentioned starches and also carboxymethyl-starch, cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such assodium alginate. Auxiliaries include, without limitation,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings, which, if desired, are resistant to gastric juices.For this purpose, concentrated saccharide solutions may be used, whichmay optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices or to provide a dosage formaffording the advantage of prolonged action, the tablet, dragee or pillcan comprise an inner dosage and an outer dosage component me latterbeing in the form of an envelope over the former. The two components canbe separated by an enteric layer, which serves to resist disintegrationin the stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, acetyl alcohol, solutions of suitable cellulose preparationssuch as acetyl-cellulose phthalate, cellulose acetate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Suitable carrier substances are organic or inorganic substances whichare suitable for enteral (e.g. oral) or parenteral administration ortopical application and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, polyethylene glycols,gelatin, carbohydrates such as lactose or starch, magnesium stearate,talc and petroleum jelly. In particular, tablets, coated tablets,capsules, syrups, suspensions, drops or suppositories are used forenteral administration, solutions, preferably oily or aqueous solutions,furthermore suspensions, emulsions or implants, are used for parenteraladministration, and ointments, creams or powders are used for topicalapplication. The products of the invention can also be lyophilized andthe lyophilizates obtained can be used, for example, for the productionof injection preparations.

The preparations indicated can be sterilized and/or can containexcipients such as lubricants, preservatives, stabilizers and/or wettingagents, emulsifiers, salts for affecting the osmotic pressure, buffersubstances, colorants, flavourings and/or aromatizers. They can, ifdesired, also contain one or more further active compounds, e.g. one ormore vitamins.

Other pharmaceutical preparations, which can be used orally includepush-fit capsules made of gelatine, as well as soft, sealed capsulesmade of gelatine and a plasticizer such as glycerol or sorbitol. Thepush-fit capsules can contain the active compounds in the form ofgranules, which may be mixed with fillers such as lactose, binders suchas starches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as fattyoils, or liquid paraffin. In addition, stabilizers may be added.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally include aqueoussolutions, suitably flavoured syrups, aqueous or oil suspensions, andflavoured emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, as well as elixirs and similar pharmaceuticalvehicles. Suitable dispersing or suspending agents for aqueoussuspensions include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatine.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400).

Aqueous injection suspensions may contain substances, which increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran, optionally, thesuspension may also contain stabilizers.

For administration as an inhalation spray, it is possible to use spraysin which the active ingredient is either dissolved or suspended in apropellant gas or propellant gas mixture (for example CO₂ orchlorofluorocarbons). The active ingredient is advantageously used herein micronized form, in which case one or more additional physiologicallyacceptable solvents may be present, for example ethanol. Inhalationsolutions can be administered with the aid of conventional inhalers.

Possible pharmaceutical preparations, which can be used rectallyinclude, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatine rectal capsules, which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

For use in medicine, the products of the present invention will be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the products of the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the products of the invention include acid additionsalts which may, for example be formed by mixing a solution of theproduct of the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulphuric acid,methanesulphonic acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the products of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g. sodium or potassiumsalts; alkaline earth metal salts, e.g. calcium or magnesium salts; andsalts formed with suitable organic bases, e.g. quaternary ammoniumsalts.

The pharmaceutical preparations can be employed as medicaments in humanand veterinary medicine. As used herein, the term “effective amount”means that amount of a drug or pharmaceutical agent that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought, for instance, by a researcher or clinician.Furthermore, the term “therapeutically effective amount” means anyamount which, as compared to a corresponding subject who has notreceived such amount, results in improved treatment, healing,prevention, or amelioration of a disease, disorder, or side effect, or adecrease in the rate of advancement of a disease or disorder.

The term also includes within its scope amounts effective to enhancenormal physiological function. Said therapeutic effective amount of oneor more of the products of the invention is known to the skilled artisanor can be easily determined by standard methods known in the art.

The products of the invention and the additional pharmacologicallyactive substances are generally administered analogously to commercialpreparations. Usually, suitable doses that are therapeutically effectivelie in the range between 0.0005 mg and 1000 mg, preferably between 0.005mg and 500 mg and especially between 0.5 mg and 100 mg per dose unit.The daily dose is preferably between about 0.001 mg/kg and 10 mg/kg ofbody weight.

Those of skill will readily appreciate that dose levels can vary as afunction of the specific compound, the severity of the symptoms and thesusceptibility of the subject to side effects. Some of the specificcompounds are more potent than others. Preferred dosages for a givencompound are readily determinable by those of skill in the art by avariety of means. A preferred means is to measure the physiologicalpotency of a given compound.

For the purpose of the present invention, all mammalian species areregarded as being comprised. In a preferred embodiment, such mammals areselected from the group consisting of “primate, human, rodent, equine,bovine, canine, feline, domestic animals, cattle, livestock, pets, cow,sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat,dog, guinea pig, hamster, rat, mouse”. More preferably, such mammals arehumans. Animal models are of interest for experimental investigations,providing a model for treatment of human diseases.

The specific dose for the individual patient depends, however, on themultitude of factors, for example on the efficacy of the specificcompounds employed, on the age, body weight, general state of health,the sex, the kind of diet, on the time and route of administration, onthe excretion rate, the kind of administration and the dosage form to beadministered, the pharmaceutical combination and severity of theparticular disorder to which the therapy relates. The specifictherapeutic effective dose for the individual patient can readily bedetermined by routine experimentation, for example by the doctor orphysician, which advises or attends the therapeutic treatment.

In the case of many disorders, the susceptibility of a particular cellto treatment with the subject compounds may be determined by in vitrotesting. Typically a culture of the cell is combined with a subjectcompound at varying concentrations for a period of time sufficient toallow the active agents to show a relevant reaction, usually betweenabout one hour and one week. For in vitro testing, cultured cells from abiopsy sample may be used.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification A1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate comprising the steps:

-   -   (a) dispersing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof in a solvent or a        solvent mixture, preferably 2-propanole, optionally under        stirring,    -   (b) converting        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof into the corresponding        hydrochloride salt by addition of etheric hydrochloric acid        solution, optionally under stirring,    -   (c) heating up the resulting dispersion or solution of step (b)        to elevated temperature T1, preferably 30° C. to 95° C., more        preferably 50° C., optionally under stirring, stirring until        crystallization begins and continuing stirring at room        temperature until completion of the crystallization process,    -   (d) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride anhydrate by solid-liquid separation, preferably        filtration, optionally subsequent washing with a solvent or a        solvent mixture, preferably ether, and optionally subsequent        drying, preferably in vacuo, optionally at elevated temperature        T2, preferably 30° C. to 95° C., more preferably 70° C.

In the course of the present invention, the terms “elevated temperature”and “elevated temperature T or T_(x)” (with x=1, 2, 3 etc.)” refer to anindividual specific temperature for a given process step or sub-stepthat is independent from any other “elevated temperature” and that canbe any temperature within the temperature range from “above roomtemperature” to “boiling temperature” of a given solvent or solventmixture and/or “melting temperature” of a given solid, educt,intermediate or product or mixture thereof, at standard pressure(approx. 1000 hPa/1000 mbar), whatever applies, whereby such anytemperature should not result in decomposition of the individual processproduct, intermediates and/or educts.

In the course of the present invention, all general and individualspecific temperatures given herein, for instance as part of the variousprocess steps and substeps, refer to temperatures at standard pressure(approx. 1000 hPa/1000 mbar). It is well-known to the person skilled inthe art that reduction or increase of pressure affects the general andindividual specific temperatures given herein, i.e. a reduction ofpressure will lead to lower respective temperatures whereas an increasewill result in higher respective temperatures. It lies within the expertknowledge of the skilled artisan to adopt the herein disclosed processsteps and substeps to lower and higher pressures, i.e. adopting therespective temperatures accordingly. Such temperature-adopted processesare within the scope and spirit of the present invention.

In the course of the present invention, the term “one or more salts of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)benzonitrile(free base)” refers to any and all salts, preferably pharmaceuticallyacceptable salts, of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base), which include, but are not limited to, acetate, adipate,alginate, arginate, aspartate, benzoate, benzolsulphonate (besylate),bisulphate, bisulphite, bromide, butyrate, bampforat, campforsulphonate,caprylate, chloride, chlorobenzoate, citrate, cyclopentanpropionate,digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulphate,ethansulphonate, fumarate, galacterate, galacturonate, glucoheptanoate,gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulphate,heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulphonate, iodide, isothionate, isobutyrate,lactate, lactobionate, malate, maleate, malonate, mandelate,metaphosphate, methanesulphonate, methylbenzoate, monohydrogenphosphate,2-naphthalinsulphonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulphate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, and toluenesulphonate.

In the course of the present invention, the term “a solvent or a solventmixture” refers to any and all solvents, preferably organic solvents andwater, more preferably pharmaceutically acceptable organic solvents andwater, which include, but are not limited to, water, methanol, ethanol,2-propanol, n-btanol, iso-butanol, acetone, methylethylketone,ethylacetate, 1,4-dioxane, diethylether, MTBE, THF, acetonitrile,dichloromethane, chloroform, DMF, cyclohexane, cyclopentane, n-hexane,n-heptane, n-pentane, toluene, o-xylene, p-xylene, DMSO, pyridine,acetic acid, anisole, butylacetate, cumene, ethylformate, formic acid,iso-butylacetate, iso-propylacetate, methylacetate, 3-methyl-1-butanol,methylisobutylketone, 2-methyl-1-propanol, 1-pentanol, propylacetate,ethylenglycole, and 1-methyl-2-pyrrolidone, as well as any and allmixtures of two or more such solvents, preferably binary mixtures, morepreferably binary mixtures of water and a pharmaceutically acceptableorganic solvent.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification NF6 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate comprising the steps:

-   -   (a) dispersing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof in a solvent or a        solvent mixture, preferably acetone, optionally under stirring,    -   (b) converting        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof into the corresponding        hydrochloride salt by addition of aqueous hydrochloric acid        solution, optionally under stirring,    -   (c) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride anhydrate by solid-liquid separation, preferably        filtration, optionally subsequent washing with a solvent or a        solvent mixture, and optionally subsequent drying, preferably in        vacuo, optionally at elevated temperature T2, preferably 30° C.        to 95° C., more preferably 65° C.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification NF4 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate comprising the steps:

-   -   (a) spreading crystalline form NF3 of        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride hydrate onto a surface, preferably a bordered        surface of a container, more preferably of a Petri dish, and        subsequently incubating it in a drying cabinet (ambient        pressure) with defined temperature, preferably 50-120% relative        humidity (RH), more preferably 60-100° C., for one or more        hours.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate comprising the steps:

-   -   (a) dispersing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof in a solvent or a        solvent mixture, preferably water, optionally under stirring,    -   (b) converting        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof into the corresponding        hydrochloride salt by addition of aqueous hydrochloric acid        solution, optionally under stirring,    -   (c1) heating up the resulting dispersion of step (b) to elevated        temperature T1, preferably 30° C. to 95° C., more preferably 60°        C., optionally under stirring, and (i) cooling down the        resulting solution, preferably to 10° C. to 40° C., more        preferably to 35° C., optionally under stirring, concentrating        the solution until crystallization begins and cooling it further        down, preferably to 0° C. to 25° C., optionally under stirring,        or (ii) solid-liquid separating, preferably filtrating it to        yield a solution, incubating the solution at room temperature        until crystallization begins and further incubating it at room        temperature for one or more hours or days, optionally under        stirring, OR    -   (c2) incubating the resulting dispersion of step (b) in an        ultrasonic bath until a clear solution is obtained, solid-liquid        separating, preferably filtrating the resulting solution and        incubating it for one or more hours or days at room temperature,        optionally under stirring,    -   (d) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride hydrate by solid-liquid separation, preferably        filtration, optionally washing with a solvent or a solvent        mixture, preferably water, and optionally subsequent drying,        preferably in vacuo, optionally at elevated temperature T2,        preferably 30° C. to 95° C., more preferably 70° C.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate comprising the steps:

-   -   (a) dispersing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride anhydrate in a solvent or a solvent mixture,        preferably water, optionally under stirring,    -   (b) incubating the resulting dispersion of step (a) at room        temperature for one or more hours or days, optionally under        stirring,    -   (c) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride hydrate by solid-liquid separation, preferably        filtration, optionally washing with a solvent or a solvent        mixture, preferably water, and optionally subsequent drying,        preferably in vacuo, optionally at elevated temperature T,        preferably 30° C. to 95° C., more preferably 70° C.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate comprising the steps:

-   -   (a) dispersing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride hydrate in a solvent or a solvent mixture,        preferably methanol or ethanol, optionally under stirring,    -   (b) incubating the resulting dispersion of step (a) at elevated        temperature T1, preferably 30° C. to 95° C., more preferably 40°        C., for one or more hours or days, optionally under stirring,        and optionally cooling it down to room temperature, optionally        under stirring,    -   (c) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride hydrate by solid-liquid separation, preferably        filtration, optionally washing with a solvent or a solvent        mixture, preferably ethanol, and optionally subsequent drying,        preferably in vacuo, optionally at elevated temperature T2,        preferably 30° C. to 95° C., more preferably 70° C.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate comprising the steps:

-   -   (a) dispersing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof in a solvent or a        solvent mixture, preferably water, optionally under stirring,    -   (b) converting        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof into the corresponding        hydrochloride salt by addition of aqueous hydrochloric acid        solution, optionally under stirring,    -   (c) heating up the resulting dispersion of step (b) to elevated        temperature T1, preferably 30° C. to 95° C., more preferably 60°        C., optionally under stirring, optionally solid-liquid        separating, preferably filtrating it to yield a solution,        incubating the solution at room temperature until        crystallization begins and further incubating it at room        temperature for one or more hours or days, optionally under        stirring,    -   (d) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride hydrate by solid-liquid separation, preferably        filtration, optionally washing with a solvent or a solvent        mixture, preferably water, and optionally subsequent drying,        preferably in vacuo, optionally at elevated temperature T2,        preferably 30° C. to 95′ C, more preferably 70° C.    -   (e) dispersing the resulting dried crystals of step (d) in a        solvent or a solvent mixture, preferably methanol or ethanol,        and incubating the resulting dispersion at room temperature for        one or more hours or days, optionally under stirring,    -   (f) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride hydrate by solid-liquid separation, preferably        filtration, optionally washing with a solvent or a solvent        mixture, preferably ethanol, and optionally subsequent drying,        preferably in vacuo, optionally at elevated temperature T3,        preferably 30° C. to 95° C., more preferably 70° C.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification NF2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate comprising the steps:

-   -   (a) dispersing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof in a solvent or a        solvent mixture, preferably water, optionally under stirring,    -   (b) converting        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof into the corresponding        hydrochloride salt by addition of hydrochloric acid solution,        optionally under stirring,    -   (c) heating up the resulting dispersion or solution of step (b)        to elevated temperature T1, preferably 30° C. to 95° C., more        preferably 60° C., optionally under stirring,    -   (d) cooling the resulting solution or dispersion down to 20-40°        C., preferably 35° C.,    -   (e) removing solvent via evaporation, preferably in a rotary        evaporator, optional under vacuum, until crystallization sets        in,    -   (f) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride hydrate by solid-liquid separation, preferably        filtration, optionally subsequent washing with a solvent,        preferably water, without further drying.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification NF2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate comprising the steps:

-   -   (a) spreading        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride anhydrate crystalline modification A1 onto a        surface, preferably a bordered surface of a container, more        preferably of a Petri dish, and subsequently incubating it in a        sealed desiccator over water or aqueous salt solutions with        defined relative humidity (RH), preferably 80-100% RH, more        preferably 94-100% RH, for one or more days or weeks.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate comprising the steps:

-   -   (a) dispersing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof in a solvent or a        solvent mixture, preferably acetone, optionally under stirring,        and optionally heating up the resulting dispersion to elevated        temperature T1, preferably 30° C. to 95° C., more preferably 60°        C., optionally under stirring,    -   (b) converting        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof into the corresponding        hydrochloride salt by addition of aqueous hydrochloric acid        solution, optionally under stirring, optionally heating up the        resulting dispersion to elevated temperature T2, preferably        30° C. to 95° C., more preferably 60° C., for one or more        minutes or hours, preferably 30 min, optionally under stirring,        and optionally adding further solvent or solvent mixture,        preferably water, optionally under stirring,    -   (c) cooling down the dispersion of step (b) to room temperature,        optionally under stirring, and incubating it at room temperature        for one or more hours or days, optionally under stirring,    -   (d) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride monohydrate by solid-liquid separation, preferably        filtration, optionally washing with a solvent or a solvent        mixture, preferably acetone or THF, and optionally subsequent        drying, preferably in vacuo, optionally at elevated temperature        T3, preferably 30° C. to 95° C., more preferably 50° C.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate comprising the steps:

-   -   (a) dispersing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof in a solvent or a        solvent mixture, preferably water, optionally under stirring,    -   (b) converting        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        (free base) or one or more salts thereof into the corresponding        hydrochloride salt by addition of aqueous hydrochloric acid        solution, optionally under stirring, heating up the resulting        dispersion to elevated temperature T1, preferably 30° C. to 100°        C., more preferably 80° C. to 100° C., optionally under        stirring, and optionally solid-liquid separating, preferably        filtrating it to obtain a solution,    -   (c) heating up again the resulting filtrate of step (b) to        elevated temperature T2, preferably 30° C. to 100° C., more        preferably 78° C. to 85° C., optionally under stirring, and        subsequently cooling it down, preferably to 0° C. to 40° C.,        more preferably to 0° C. to 27° C., over one or more hours or        days, optionally under stirring, and optionally cooling it        further down, preferably to 0° C. to 25° C., more preferably to        20° C., optionally under stirring,    -   (d) isolating precipitated        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride monohydrate by solid-liquid separation, preferably        filtration, optionally washing with a solvent or a solvent        mixture, preferably water, THF or acetone, and optionally        subsequent drying, preferably in vacuo, optionally at elevated        temperature T3, preferably 30° C. to 95° C., more preferably        50° C. to 55° C.

In a preferred embodiment, a process for manufacturing crystallinemodification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate according to above aspects and embodiments isprovided, wherein in step (b)3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) or one or more salts thereof is converted into thecorresponding hydrochloride salt by addition of one or more chloridesalts selected from the group consisting of: “alkaline metal chloridesalt, such as NaCl, KCl and LiCl; alkaline earth metal chloride salt,such as CaCl₂ and MgCl₂; ammonium chloride salt (NH₄Cl), quaternaryorganic ammonia chloride salt, such as ethanolammonium chloride anddiethylammonium chloride; transition metal chloride salt, such as FeCl₂and CuCl₂”.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing crystallinemodification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate comprising the steps:

-   -   (a) re-crystallizing        3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile        hydrochloride monohydrate from a solvent or a solvent mixture,        optionally under stirring.

The processes for manufacturing the crystalline modifications of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate, hydrate and monohydrate, in particular forcrystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate, are surprisingly characterized by a superiorproduct quality due to crystallization from aqueous solvents or aqueoussolvent mixtures, preferably water. Further, these processes aresurprisingly characterized by superior yields as well as increasedproduct stability. In particular, crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate represents the thermodynamically most stablecrystalline modification that does not convert itself into less stablecrystalline modifications during storage as pharmaceutical formulation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the powder X-ray diffractogram of crystallinemodification A1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 2 depicts the FT-IR spectrum of crystalline modification A1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 3 depicts the FT-Raman spectrum of crystalline modification A1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 4 depicts the DSC scan profile (Perkin-Elmer Diamond DSC, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification A1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 5 depicts the TGA scan profile (Perkin-Elmer Pyris TGA1, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification A1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 6 depicts the Water Vapour Sorption Isotherm (25° C.) (SMS DVS 1)of crystalline modification A1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 7 depicts the powder X-ray diffractogram of crystallinemodification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 8 depicts the FT-IR spectrum of crystalline modification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 9 depicts the FT-Raman spectrum of crystalline modification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 10 depicts the DSC scan profile (Mettler-Toledo DSC 821, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 11 depicts the TGA scan profile (Perkin-Elmer Pyris TGA1, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 12 depicts the Water Vapour Sorption Isotherm (25° C.) (SMS DVSIntrinsic) of crystalline modification H1 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 13 depicts the powder X-ray diffractogram of crystallinemodification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 14 depicts the FT-IR spectrum of crystalline modification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 15 depicts the FT-Raman spectrum of crystalline modification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 16 depicts the DSC scan profile (Mettler-Toledo DSC 821, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 17 depicts the TGA scan profile (Perkin-Elmer Pyris TGA1, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 18 depicts the Water Vapour Sorption Isotherm (25° C.) (SMS DVSAdvantage) of crystalline modification NF3 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 19 depicts the powder X-ray diffractogram of crystallinemodification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

FIG. 20 depicts single crystal X-Ray Structure data of crystallinemodification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate viewed along c-axis.

FIG. 21 depicts the FT-IR spectrum of crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

FIG. 22 depicts the FT-Raman spectrum of crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

FIG. 23 depicts the DSC scan profile (Mettler-Toledo DSC 821, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

FIG. 24 depicts the TGA scan profile (Mettler-Toledo TGA 851, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

FIG. 25 depicts the Water Vapour Sorption Isotherm (25° C.) (SMS DVSIntrinsic) of crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

FIG. 26 depicts a powder X-ray diffractogram of compound “A7” accordingto Example 4 of PCT/EP2008/005508.

FIG. 27 depicts another powder X-ray diffractogram of compound “A7”according to Example 4 of PCT/EP2008/005508.

FIG. 28 depicts the powder X-ray diffractogram of crystallinemodification NF6 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 29 depicts the FT-IR spectrum of crystalline modification NF6 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 30 depicts the FT-Raman spectrum of crystalline modification NF6 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 31 depicts the DSC scan profile (Mettler-Toledo DSC821, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification NF6 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 32 depicts the TGA scan profile (Perkin-Elmer Pyris TGA1, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification NF6 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 33 depicts the Water Vapour Sorption Isotherm (25° C.) (SMS DVSIntrinsic) of crystalline modification NF6 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 34 depicts the powder X-ray diffractogram of crystallinemodification NF4 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate.

FIG. 35 depicts the powder X-ray diffractogram of crystallinemodification NF2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 36 depicts the DSC scan profile (Mettler-Toledo DSC821, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification NF2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 37 depicts the TGA scan profile (Perkin-Elmer Pyris TGA1, 5 K/min,nitrogen purge gas 50 mL/min) of crystalline modification NF2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

FIG. 38 depicts the Water Vapour Sorption Isotherm (25° C.) (SMS DVSIntrinsic) of crystalline modification NF2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate.

Even without further details, it is assumed that a person skilled in theart will be able to utilise the above description in the broadest scope.The preferred embodiments should therefore merely be regarded asdescriptive disclosure, which is absolutely not limiting in any way.

The contents of all cited references are hereby incorporated byreference in their entirety. The invention is explained in more detailby means of the following examples without, however, being restrictedthereto.

EXAMPLES Example 1 Production of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification A1 Method 1

Approx. 200 mg of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in 5 mL warm 2-propanole. After addition ofapprox. 0.1 mL etheric HCl solution (10%), a clear solution was formed,which was further agitated at 50° C. until crystallisation set in.Agitation was continued at room temperature until completion of thecrystallisation process. The obtained crystals were filtered and washedwith ether.

¹H-NMR (d₆-DMSO): δ [ppm]=1.60 (m, 2H), 2.00 (m, 2H), 2.07 (m, 1H), 2.75(d, 3H), 2.97 (m, 2H), 3.45 (m, 2H), 4.10 (d, 2H), 5.45 (s, 2H), 7.16(d, 1H), 7.50 (bm, 2H), 7.73 (t, 1H), 7.93 (m, 1H), 8.18 (d, 1H), 8.25(bm, 2H), 8.38 (m, 2H), 8.67 (s, 2H), 9.90 (bs, 1H).

Ion Chromatography: 6.4 wt % CI (equivalent to molar acid:base ratio of0.96)

Method 2

Approx. 2 g of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in 5 mL warm 2-propanole. After addition ofapprox. 2 mL etheric HCl solution (10%), a clear solution was formed,which was further agitated at 50° C. until crystallisation set in.Agitation was continued at room temperature until completion of thecrystallisation process. The obtained crystals were filtered and washedwith ether.

¹H-NMR (de-DMSO): δ [ppm]=1.60 (m, 2H), 2.00 (m, 2H), 2.07 (m, 1H), 2.75(d, 3H), 2.97 (m, 2H), 3.45 (m, 2H), 4.10 (d, 2H), 5.45 (s, 2H), 7.15(d, 1H), 7.50 (bm, 2H), 7.72 (t, 1H), 7.93 (m, 1H), 8.18 (d, 1H), 8.24(bm, 2H), 8.39 (m, 2H), 8.66 (s, 2H), 10.05 (bs, 1H).

Ion Chromatography: 5.9 wt % CI (equivalent to molar acid:base ratio of0.88 based on the anhydrous HCl salt)

Example 2 Production of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in its crystalline modification H1 Method 1

Approx. 44.75 g of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in 430 mL DI water, and approx. 105 mL 1 Naqueous HCl solution was added. The dispersion was heated to 60° C.,resulting in an opaque solution. The solution was cooled down to 35° C.and concentrated in a rotary evaporator (w/o vacuum) untilcrystallisation was observed. The dispersion was cooled in ice water,and finally filtered. Crystals were dried under vacuum at 70° C.

¹H-NMR (de-DMSO): δ [ppm]=1.59 (m, 2H), 1.99 (m, 2H), 2.06 (m, 1H), 2.73(s, 3H), 2.97 (m, 2H), 3.43 (m, 2H), 4.10 (d, 2H), 5.45 (s, 2H), 7.18(d, 1H), 7.50 (bm, 2H), 7.71 (t, 1H), 7.93 (m, 1H), 8.18 (d, 1H), 8.23(bm, 2H), 8.38 (m, 2H), 8.66 (s, 2H), 9.98 (bs, 1H).

Ion Chromatography: 6.4 wt % CI (equivalent to molar acid:base ratio of1.01 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 5.2 wt % water.

Method 2

Approx. 5.12 g of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 44 mL DI water and approx. 11 mL 1N aqueous HCl solution. The dispersion was put in an ultrasonic bathuntil a clear solution was obtained, and filtered thereafter. The clearsolution was agitated overnight at room temperature. The resultingcrystals were filtered, and dried.

¹H-NMR (d₆-DMSO): δ [ppm]=1.61 (m, 2H), 1.99 (m, 2H), 2.06 (m, 1H), 2.74(s, 3H), 2.95 (m, 2H), 3.45 (m, 2H), 4.10 (d, 2H), 5.45 (s, 2H), 7.17(d, 1H), 7.50 (bm, 2H), 7.72 (t, 1H), 7.93 (m, 1H), 8.18 (d, 1H), 8.23(bm, 2H), 8.37 (m, 2H), 8.65 (s, 2H), 10.05 (bs, 1H).

Ion Chromatography: 6.0 wt % CI (equivalent to molar acid:base ratio of0.97 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 7.9 wt % water.

Method 3

Approx. 495 mg of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 3.9 mL DI water and approx. 1.1 mL1 N aqueous HCl solution. The dispersion was heated and the warm (40-80°C.) dispersion filtered to yield a clear solution. The clear solutionwas left at room temperature until crystallisation started after approx.4 hours. The resulting dispersion was filtered. Crystals were washedwith DI water, and dried under vacuum.

¹H-NMR (d₆-DMSO): δ [ppm]=1.58 (m, 2H), 1.98 (m, 2H), 2.05 (m, 1H), 2.74(s, 3H), 2.94 (m, 2H), 3.45 (m, 2H), 4.10 (d, 2H), 5.44 (s, 2H), 7.16(d, 1H), 7.50 (bm, 2H), 7.72 (t, 1H), 7.93 (m, 1H), 8.18 (d, 1H), 8.25(bm, 2H), 8.37 (m, 2H), 8.65 (s, 2H), 9.78 (bs, 1H).

Ion Chromatography: 6.0 wt % CI (equivalent to molar acid:base ratio of0.95 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 6.2 wt % water.

Method 4

Approx. 985 mg of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 8 mL DI water and approx. 2.1 mL 1N aqueous HCl solution. The dispersion was heated and the warmdispersion filtered to yield a clear solution. The clear solution wasleft at room temperature until crystallisation set in. After leaving theexperiment over night, the resulting dispersion was filtered. Crystalswere washed with DI water, and dried under vacuum.

¹H-NMR (de-DMSO): δ [ppm]=1.57 (m, 2H), 1.98 (m, 2H), 2.05 (m, 1H), 2.74(s, 3H), 2.95 (m, 2H), 3.43 (m, 2H), 4.09 (d, 2H), 5.44 (s, 2H), 7.16(d, 1H), 7.50 (bm, 2H), 7.73 (t, 1H), 7.93 (m, 1H), 8.17 (d, 1H), 8.24(bm, 2H), 8.37 (m, 2H), 8.65 (s, 2H), 9.77 (bs, 1H).

Ion Chromatography: 6.0 wt % CI (equivalent to molar acid:base ratio of0.97 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 7.9 wt % water.

Method 5

Approx. 700 mg of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate crystalline modification H1 were dispersed inapprox. 7 mL DI water agitated over several days at room temperature.The resulting dispersion was filtered. Crystals were washed with DIwater, and dried under vacuum.

¹H-NMR (de-DMSO): δ [ppm]=1.57 (m, 2H), 1.98 (m, 2H), 2.05 (m, 1H), 2.74(s, 3H), 2.94 (m, 2H), 3.43 (m, 2H), 4.10 (d, 2H), 5.44 (s, 2H), 7.17(d, 1H), 7.49 (bm, 2H), 7.73 (t, 1H), 7.93 (m, 1H), 8.18 (d, 1H), 8.24(bm, 2H), 8.37 (m, 2H), 8.66 (s, 2H), 9.68 (bs, 1H).

Ion Chromatography: 5.7 wt % CI (equivalent to molar acid:base ratio of0.90 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 6.1 wt % water.

Example 3 Production of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in its crystalline modification NF3 Method 1

Approx. 1.1 g of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate crystalline modification H1 were dispersed inapprox. 20 mL ethanol and agitated as slurry at 40 C for several days.The dispersion was then filtered and resulting crystals washed withethanol and dried under vacuum.

¹H-NMR (de-DMSO): δ [ppm]=1.65 (m, 2H), 1.98 (m, 2H), 2.06 (m, 1H), 2.73(s, 3H), 2.98 (m, 2H), 3.44 (m, 2H), 4.10 (d, 2H), 5.44 (s, 2H), 7.16(d, 1H), 7.49 (bm, 2H), 7.72 (t, 1H), 7.94 (m, 1H), 8.18 (d, 1H), 8.24(bm, 2H), 8.38 (m, 2H), 8.65 (s, 2H), 10.52 (bs, 1H).

Ion Chromatography: 6.0 wt % CI (equivalent to molar acid:base ratio of0.96 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 6.6 wt % water.

Method 2

Approx. 495 mg of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 3.9 mL DI water and approx. 1.1 mL1 N aqueous HCl solution. The dispersion was heated and the warmdispersion filtered to yield a clear solution. The clear solution wasleft at room temperature until crystallisation set in. After approx. 4hours, the resulting dispersion was filtered. Crystals were washed withDI water, and dried under vacuum. Approx 346 mg of the dried crystalswere dispersed in approx. 3 mL ethanol and agitated as slurry at roomtemperature for several days. The dispersion was then filtered andresulting crystals washed with ethanol and dried under vacuum.

¹H-NMR (de-DMSO): δ [ppm]=1.58 (m, 2H), 1.99 (m, 2H), 2.06 (m, 1H), 2.73(s, 3H), 2.96 (m, 2H), 3.43 (m, 2H), 4.10 (d, 2H), 5.45 (s, 2H), 7.17(d, 1H), 7.49 (bm, 2H), 7.72 (t, 1H), 7.93 (m, 1H), 8.18 (d, 1H), 8.24(bm, 2H), 8.39 (m, 2H), 8.67 (s, 2H), 9.80 (bs, 1H).

Ion Chromatography: 5.7 wt % Cl (equivalent to molar acid:base ratio of0.92 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 7.9 wt % water.

Method 3

Approx. 100 mg of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate crystalline modification H2 were dispersed inapprox. 0.6 mL methanol and shaken as slurry at room temperature at 1000rpm for 1 day. The dispersion was then filtered and resulting crystalswere dried at ambient conditions on the filter.

¹H-NMR (de-DMSO): δ [ppm]=1.58 (m, 2H), 2.00 (m, 2H), 2.06 (m, 1H), 2.75(s, 3H), 2.98 (m, 2H), 3.46 (m, 2H), 4.10 (d, 2H), 5.46 (s, 2H), 7.16(d, 1H), 7.49 (bm, 2H), 7.73 (t, 1H), 7.94 (m, 1H), 8.18 (d, 1H), 8.24(bm, 2H), 8.39 (m, 2H), 8.66 (s, 2H), 9.77 (bs, 1H).

Ion Chromatography: 5.6 wt % Cl (equivalent to molar acid:base ratio of0.92 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 9.6 wt % water.

Method 4

Approx. 1.1 g of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate crystalline modification H1 were dispersed inapprox. 20 mL ethanol and agitated as slurry at 40 C for 1 day. Thedispersion was then cooled to room temperature and filtered. Resultingcrystals were washed with ethanol and dried under vacuum.

¹H-NMR (de-DMSO): δ [ppm]=1.57 (m, 2H), 1.98 (m, 2H), 2.05 (m, 1H), 2.74(s, 3H), 2.95 (m, 2H), 3.44 (m, 2H), 4.10 (d, 2H), 5.45 (s, 2H), 7.15(d, 1H), 7.48 (bm, 2H), 7.73 (t, 1H), 7.93 (m, 1H), 8.17 (d, 1H), 8.23(bm, 2H), 8.37 (m, 2H), 8.65 (s, 2H), 9.70 (bs, 1H).

Ion Chromatography: 5.3 wt % CI (equivalent to molar acid:base ratio of0.81 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 2.0 wt % water.

Example 4 Production of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate in its crystalline modification H2 Method 1

Approx. 636 mg of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 7 mL acetone and heated. Approx.1.4 mL 1 N aqueous HCl solution were added, resulting in a clearsolution with subsequent crystallisation setting in. The resultingdispersion was agitated at room temperature for 16 hours, andsubsequently filtered. The resulting crystals were dried under vacuum at70° C.

¹H-NMR (de-DMSO): δ [ppm]=1.60 (m, 2H), 1.98 (m, 2H), 2.07 (m, 1H), 2.74(s, 3H), 2.95 (m, 2H), 3.44 (m, 2H), 4.10 (s, 2H), 5.45 (s, 2H), 7.15(d, 1H), 7.48 (bm, 2H), 7.72 (t, 1H), 7.93 (m, 1H), 8.18 (d, 1H), 8.24(bm, 2H), 8.38 (m, 2H), 8.65 (s, 2H), 9.82 (bs, 1H).

Ion Chromatography: 5.9 wt % CI (equivalent to molar acid:base ratio of0.93 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 5.5 wt % water.

Method 2

Approx. 106 g of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 1.1 L acetone and approx. 237 mL 1N aqueous HCl. The dispersion was heated to 60° C. for 0.5 h, withfurther addition of approx. 18.5 mL DI water. The dispersion was thencooled to room temperature and agitated over night at room temperature.The dispersion was then filtered, and resulting crystals washed withacetone and dried under vacuum.

¹H-NMR (de-DMSO): δ [ppm]=1.65 (m, 2H), 1.98 (m, 2H), 2.07 (m, 1H), 2.73(s, 3H), 2.96 (m, 2H), 3.44 (m, 2H), 4.10 (d, 2H), 5.45 (s, 2H), 7.16(d, 1H), 7.49 (bm, 2H), 7.72 (t, 1H), 7.93 (m, 1H), 8.17 (d, 1H), 8.24(bm, 2H), 8.38 (m, 2H), 8.65 (s, 2H), 10.30 (bs, 1H).

Ion Chromatography: 6.7 wt % CI (equivalent to molar acid:base ratio of1.04 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 3.7 wt % water.

Method 3

Approx. 1.04 kg of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 9 L DI water and approx. 2.27 L 1N aqueous HCl. The dispersion was heated to 80° C., with subsequent warmfiltration to yield a clear solution. The filtrate was heated to 78° C.,and slowly cooled over night down to 27° C. The resulting dispersion wasfurther cooled down to 20° C., and filtered. The resulting crystals weredried under vacuum at 55° C.

¹H-NMR (de-DMSO): δ [ppm]=1.62 (m, 2H), 1.99 (m, 2H), 2.08 (m, 1H), 2.75(s, 3H), 2.98 (m, 2H), 3.43 (m, 2H+H2O), 4.12 (s, 2H), 5.45 (s, 2H),7.15 (d, 1H), 7.50 (bm, 2H), 7.73 (t, 1H), 7.93 (m, 1H), 8.17 (d, 1H),8.24 (bm, 2H), 8.38 (m, 2H), 8.65 (s, 2H), 9.98 (bs, 1H).

Ion Chromatography: 5.7 wt % CI (equivalent to molar acid:base ratio of0.91 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 6.3 wt % water.

Method 4

Approx. 7.5 g of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 65.5 g DI water and approx. 2.25 gaqueous HCl solution (25%). The dispersion was heated to 90° C., withsubsequent warm filtration to yield a clear solution. The filtrate washeated to 85° C., and slowly cooled down to 20° C. at 0.1 K/min. Theresulting dispersion was filtered at room temperature. The resultingcrystals were washed with DI water and acetone and dried under vacuum at50° C.

¹H-NMR (d₆-DMSO): δ [ppm]=1.58 (m, 2H), 1.98 (m, 2H), 2.06 (m, 1H), 2.74(s, 3H), 2.95 (m, 2H), 3.44 (m, 2H), 4.10 (d, 2H), 5.45 (s, 2H), 7.16(d, 1H), 7.49 (bm, 2H), 7.72 (t, 1H), 7.93 (m, 1H), 8.18 (d, 1H), 8.25(bm, 2H), 8.38 (m, 2H), 8.65 (s, 2H), 9.74 (bs, 1H).

Ion Chromatography: 5.7 wt % CI (equivalent to molar acid:base ratio of1.03 based on HCl salt with observed water content as specified below).

Karl-Fischer-Titration: 5.7 wt % water.

Example 5 Production of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification NF6 Method 1

Approx. 511 mg of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 75 mL acetone. After addition ofapprox. 1.1 mL aqueous hydrochloric acid solution, precipitationoccurred. The dispersion was then filtered and resulting crystals weredried at under vacuum at 65° C.

¹H NMR (500 MHz, DMSO) δ=10.28 (s br, 1H), 8.64 (s, 2H), 8.44-8.31 (m,2H), 8.29-8.20 (m, 2H), 8.17 (d, J=9.8, 1H), 7.93 (d, J=7.8, 1H), 7.72(t, J=7.9, 1H), 7.53-7.43 (m, 2H), 7.16 (d, J=9.7, 1H), 5.45 (s, 2H),4.35-3.86 (m, 2H), 3.62-3.36 (m, 2H), 3.10-2.86 (m, 2H), 2.71 (s, 3H),2.20-2.02 (m, 1H), 2.01-1.91 (m, 2H), 1.76-1.49 (m, 2H).

Ion Chromatography: 6.6 wt % CI (equivalent to molar acid:base ratio of0.98)

Karl-Fischer-Titration: 0.8 wt % water.

Example 6 Production of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification NF4 Method 1

Approx. 20 mg of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate, crystalline modification NF3, were placed in atemperature chamber of an Powder X-Ray Diffraction (PXRD) instrument.The sample was heated from 30° C. to 60° C. in increments of 10° C.,with approx. dwell times of 30 minutes at each temperature.

Method 2

Approx. 20 mg of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate, crystalline modification NF3, were spread on apetri dish, and placed in a drying cabinet at 60° C. (ambient pressure)for 4 hours.

Example 7 Production of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in its crystalline modification NF2 Method 1

Approx. 44.8 g of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile(free base) were dispersed in approx. 440 mL water. After addition of 5mL aqueous hydrochloric acid (1 N) and further 90 mL water, theresulting dispersion was heated to 60° C. The resulting solution wascooled to 35° C. Solvent was evaporated in a rotary evaporator atambient pressure until crystallisation set-in. The resulting dispersionwas then cooled in an ice-batch and filtered, without further dryingprocedures.

Method 2

Approx. 50 mg of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification A1 were spreadonto a Petri dish and stored in a closed desiccator over pure DI water(100% relative humidity atmosphere) for 3 weeks.

Example 8 Structural and physico-chemical characterization of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification A1

A Powder X-Ray Diffraction pattern of crystalline modification A1 wasobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.9.33, and is characterized by thefollowing X-ray powder diffractogram (Cu—Kα₁ radiation, λ=1.5406 Å, StoeStadiP 611 KL diffractometer) depicted in FIG. 1.

Crystalline modification A1 is characterized by the following XRD data:

Powder X-ray diffractogram peak list: °2θ (Cu-Kα₁ radiation) Peak No.d/Å ±0.1° 1 20.08 4.4 2 8.55 10.3 3 7.43 11.9 4 5.70 15.5 5 5.56 15.9 64.99 17.8 7 4.86 18.2 8 4.74 18.7 9 4.55 19.5 10 4.46 19.9 11 4.27 20.812 4.10 21.6 13 3.91 22.7 14 3.82 23.3 15 3.65 24.3

Crystalline modification A1 was further characterized by IR- andRaman-spectroscopy. FT-Raman and FT-IR spectra were obtained by standardtechniques as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.24 and 2.02.48. For measurement of the FT-IR andFT-Raman-spectra a Bruker Vector 22 and a Bruker RFS 100 spectrometerwere used. FT-IR spectra were base-line corrected using Bruker OPUSsoftware. FT-Raman spectra were vector normalized using the samesoftware.

An FT-IR spectrum was obtained using a KBr pellet as sample preparationtechnique. The FT-IR spectrum is depicted in FIG. 2 and the bandpositions are given below.

Crystalline modification A1 IR band positions ±2 cm⁻¹ (relativeintensity*) *“s”=strong (transmittance≦50%), “m”=medium(50%<transmittance≦70%), “w”=weak (transmittance>70%)

2951 cm⁻¹ (w), 2914 cm⁻¹ (w), 2472 cm⁻¹ (w), 2224 cm⁻¹ (w), 1671 cm⁻¹(s), 1597 cm⁻¹ (w), 1579 cm⁻¹ (m), 1548 cm⁻¹ (w), 1433 cm⁻¹ (s), 1281cm⁻¹ (m), 1153 cm⁻¹ (w), 1059 cm⁻¹ (w), 1012 cm⁻¹ (w), 905 cm⁻¹ (w), 846cm⁻¹ (w), 822 cm⁻¹ (w), 761 cm⁻¹ (w), 697 cm⁻¹ (w)

An FT-Raman spectrum is depicted in FIG. 3 and the band positions aregiven below.

Crystalline modification A1 Raman band positions+2 cm⁻¹ (relativeintensity*): *“s”=strong (relative Raman intensity≧0.04), “m”=medium(0.04>relative Raman intensity≧0.02), “w”=weak (relative Ramanintensity<0.02)

3057 cm⁻¹ (m), 2960 cm⁻¹ (w), 2895 cm⁻¹ (w), 2224 cm⁻¹ (s), 1598 cm⁻¹(s), 1582 cm⁻¹ (s), 1489 cm⁻¹ (m), 1453 cm⁻¹ (m), 1434 cm⁻¹ (s), 1328cm⁻¹ (s), 1314 cm⁻¹ (m), 1289 cm⁻¹ (m), 1175 cm⁻¹ (w), 1002 cm⁻¹ (m),996 cm⁻¹ (m), 849 cm⁻¹ (w), 833 cm⁻¹ (w)

Crystalline modification A1 is a crystalline anhydrous form, which isfurther characterized by the following physical properties:

-   -   Thermal behavior shows a melting peak at approx. 236° C., with a        very small mass loss up to the melting temperature. DSC profile        (Perkin-Elmer Diamond DSC, 5 K/min, nitrogen purge gas 50        mL/min) and TGA profile (Perkin-Elmer Pyris TGA1, 5 K/min,        nitrogen purge gas 50 mL/min) are displayed in FIGS. 4 and 6,        respectively.    -   Water Vapor Sorption behavior shows very small water uptake        levels upon adsorption in the range 0-90% relative humidity        (RH), and strongly hygroscopic behavior at 98% RH (water uptake        levels >15 wt %). Water Vapor Sorption isotherm (25° C.) of        crystalline modification A1 is displayed in FIG. 6.    -   Solubility of crystalline modification A1 in Simulated Gastric        Fluid (acc. to USP) at ambient conditions (approx. 20-25° C.)        was determined to be approx. 220 μg/mL.

Example 9 Structural and physico-chemical characterization of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in its crystalline modification H1

A Powder X-Ray Diffraction pattern of crystalline modification H1 wasobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.9.33, and is characterized by thefollowing X-ray powder diffractogram (Cu—Kα₁ radiation, λ=1.5406 Å, StoeStadiP 611 KL diffractometer) depicted in FIG. 7.

Crystalline modification H1 is characterized by the following XRD data:

Powder X-ray diffractogram peak list: °2θ (Cu-Kα₁ radiation) Peak No.d/Å ±0.1° 1 14.88 5.9 2 9.99 8.8 3 7.83 11.3 4 7.25 12.2 5 6.10 14.5 65.84 15.2 7 5.52 16.0 8 5.38 16.5 9 4.92 18.0 10 4.12 21.6 11 3.80 23.412 3.57 24.9 13 3.49 25.5 14 3.30 27.0 15 2.95 30.3

Crystalline modification H1 was further characterized by IR- andRaman-spectroscopy. FT-Raman and FT-IR spectra were obtained by standardtechniques as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.24 and 2.02.48. For measurement of the FT-IR andFT-Raman-spectra a Bruker Vector 22 and a Bruker RFS 100 spectrometerwere used. FT-IR spectra were base-line corrected using Bruker OPUSsoftware. FT-Raman spectra were vector normalized using the samesoftware.

An FT-IR spectrum was obtained using a KBr pellet as sample preparationtechnique. The FT-IR spectrum is depicted in FIG. 8 and the bandpositions are given below.

Crystalline modification H1 IR band positions ±2 cm⁻¹ (relativeintensity*) *“s”=strong (transmittance≦50%), “m”=medium(50%<transmittance≦70%), “w”=weak transmittance>70%)

3519 cm⁻¹ (m), 3415 cm⁻¹ (m), 3032 cm⁻¹ (w), 2956 cm⁻¹ (m), 2521 cm⁻¹(m), 2232 cm⁻¹ (m), 1669 cm⁻¹ (s), 1651 cm⁻¹ (s), 1577 cm⁻¹ (s), 1551cm⁻¹ (m), 1438 cm⁻¹ (s), 1282 cm⁻¹ (s), 1159 cm⁻¹ (m), 1070 cm⁻¹ (w),1004 cm⁻¹ (m), 957 cm⁻¹ (m), 850 cm⁻¹ (m), 801 cm⁻¹ (m), 773 cm⁻¹ (m),682 cm⁻¹ (m)

An FT-Raman spectrum is depicted in FIG. 9 and the band positions aregiven below.

Crystalline modification H1 Raman band positions ±2 cm⁻¹ (relativeintensity*): *“s”=strong (relative Raman intensity≧0.04), “m”=medium(0.04>relative Raman intensity≧0.02), “w”=weak (relative Ramanintensity<0.02)

3065 cm⁻¹ (m), 2965 cm⁻¹ (m), 2936 cm⁻¹ (w), 2232 cm⁻¹ (s), 1586 cm⁻¹(s), 1485 cm⁻¹ (w), 1453 cm⁻¹ (m), 1429 cm⁻¹ (m), 1332 cm⁻¹ (s), 1295cm⁻¹ (m), 1281 cm⁻¹ (m), 1192 cm⁻¹ (w), 1002 cm⁻¹ (m), 851 cm⁻¹ (w), 834cm⁻¹ (w)

Crystalline modification H1 is a crystalline hydrate form, which isfurther characterized by the following physical properties:

-   -   Thermal behavior shows dehydration of hydrate water from approx.        50-120° C. upon heating with loss of crystallinity and        subsequent re-crystallisation of the anhydrous form. At approx.        230° C. melting occurs. DSC profile (Mettler-Toledo DSC 821, 5        K/min, nitrogen purge gas 50 mL/min) and TGA profile        (Perkin-Elmer Pyris TGA1, 5 K/min, nitrogen purge gas 50 mL/min)        are displayed in FIGS. 10 and 11, respectively.    -   Water Vapor Sorption behavior shows strongly hygroscopic        behaviour at relative humidity (RH) levels >70% (with water        uptake levels of >15 wt % at 80% RH). Water Vapor Sorption        isotherm (25° C.) of crystalline modification H1 is displayed in        FIG. 12.    -   Kinetic Solubility (after 60 minutes) of crystalline        modification H1 in 0.1N HCl (pH 1.0) at room temperature        (approx. 20-25° C.) was determined to be approx. 3 μg/mL.

Example 10

Structural and physico-chemical characterization of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in its crystalline modification NF3

A Powder X-Ray Diffraction pattern of crystalline modification NF3 wasobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.9.33, and is characterized by thefollowing X-ray powder diffractogram (Cu—Kα₁ radiation, λ=1.5406 Å, StoeStadiP 611 KL diffractometer) depicted in FIG. 13.

Crystalline modification NF3 is characterized by the following XRD data:

Powder X-ray diffractogram peak list: °2θ (Cu—Kα₁ Peak No. d/Åradiation) ± 0.1° 1 14.83 6.0 2 8.96 9.9 3 6.92 12.8 4 5.62 15.7 5 5.4416.3 6 5.26 16.9 7 4.38 20.3 8 4.32 20.6 9 3.79 23.5 10 3.69 24.1 113.59 24.8 12 3.55 25.1 13 3.45 25.8 14 3.35 26.6 15 3.22 27.7

Crystalline modification NF3 was further characterized by IR- andRaman-spectroscopy. FT-Raman and FT-IR spectra were obtained by standardtechniques as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.24 and 2.02.48. For measurement of the FT-IR andFT-Raman-spectra a Bruker Vector 22 and a Bruker RFS 100 spectrometerwere used. FT-IR spectra were base-line corrected using Bruker OPUSsoftware. FT-Raman spectra were vector normalized using the samesoftware.

An FT-IR spectrum was obtained using a KBr pellet as sample preparationtechnique. The FT-IR spectrum is depicted in FIG. 14 and the bandpositions are given below.

Crystalline modification NF3 IR band positions ±2 cm⁻¹ (relativeintensity*) *“s”=strong (transmittance≦50%), “m”=medium(50%<transmittance≦70%), “w”=weak (transmittance>70%)

3437 cm⁻¹ (s), 2941 cm⁻¹ (m), 2697 cm⁻¹ (m), 2232 cm⁻¹ (m), 1661 cm⁻¹(s), 1578 cm⁻¹ (s), 1551 cm⁻¹ (m), 1436 cm⁻¹ (s), 1284 cm⁻¹ (s), 1160cm⁻¹ (m), 1001 cm⁻¹ (m), 954 cm⁻¹ (m), 842 cm⁻¹ (w), 813 cm⁻¹ (m), 770cm⁻¹ (m), 685 cm⁻¹ (m)

An FT-Raman spectrum is depicted in FIG. 15 and the band positions aregiven below.

Crystalline modification NF3 Raman band positions ±2 cm⁻¹ (relativeintensity*): *“s”=strong (relative Raman intensity≧0.04), “m”=medium(0.04>relative Raman intensity≧0.02), “w”=weak (relative Ramanintensity<0.02).

3064 cm⁻¹ (m), 2944 cm⁻¹ (m), 2891 cm⁻¹ (w), 2232 cm⁻¹ (s), 1599 cm⁻¹(s), 1585 cm⁻¹ (s), 1484 cm⁻¹ (w), 1450 cm⁻¹ (m), 1432 cm⁻¹ (s), 1336cm⁻¹ (m), 1328 cm⁻¹ (s), 1280 cm⁻¹ (w), 1187 cm⁻¹ (w), 1002 cm⁻¹ (m),833 cm⁻¹ (w)

Crystalline modification NF3 is a crystalline hydrate form, which isfurther characterized by the following physical properties:

-   -   Thermal behavior shows dehydration of hydrate water from approx.        40-120° C. upon heating with loss of crystallinity and        subsequent re-crystallisation of the anhydrous form. At approx.        230° C. melting occurs. DSC profile (Mettler-Toledo DSC 821, 5        K/min, nitrogen purge gas 50 mL/min) and TGA profile        (Perkin-Elmer Pyris TGA1, 5 K/min, nitrogen purge gas 50 mL/min)        are displayed in FIGS. 16 and 17, respectively.    -   Water Vapor Sorption behavior shows continuous water uptake        levels up to approx. 9 wt % at 98% relative humidity (RH). Acc.        to Ph. Eur. criteria, Form NF3 can be classified as        slightly-hygroscopic. Under dry conditions, dehydration of        hydrate water occurs. Water Vapor Sorption isotherm (25° C.) of        crystalline modification NF3 is displayed in FIG. 18.    -   Thermodynamic Solubility of crystalline modification NF3 in 0.1N        HCl (pH 1.0) at 37° C. was determined to be approx. 70 μg/mL.

Example 11 Structural and physico-chemical characterization of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate in its crystalline modification H2

A Powder X-Ray Diffraction pattern of crystalline modification H2 wasobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.9.33, and is characterized by thefollowing X-ray powder diffractogram (Cu—Kα₁ radiation, λ=1.5406 Å, StoeStadiP 611 KL diffractometer) depicted in FIG. 19.

Crystalline modification H2 is characterized by the following XRD data:

Powder X-ray diffractogram peak list: °2θ (Cu—Kα₁ Peak No. d/Åradiation) ± 0.1° 1 8.71 10.1 2 8.22 10.8 3 7.59 11.6 4 6.78 13.0 5 6.5813.5 6 5.73 15.4 7 4.98 17.8 8 4.84 18.3 9 4.68 19.0 10 4.43 20.0 114.35 20.4 12 3.73 23.9 13 3.64 24.5 14 3.39 26.3 15 3.13 28.5

Single crystal X-Ray Structure data were obtained on crystallinemodification H2 as well (XCalibur diffractometer from Oxford Diffractionequipped with graphite monochromator and CCD Detector using Mo K_(α)radiation at 301 K). The single crystal structure of crystallinemodification H2 viewed along c-axis is depicted in FIG. 20.

Crystalline modification H2 crystallizes in the monoclinic space groupP2₁/c with the lattice parameters a=9.8 Å, b=31.0 Å, c=10.1 Å, andβ=117.5° (with α=γ=90°). From the single crystal structure it is obviousthat crystalline modification H2 represents a stoichiometricmonohydrate.

Crystalline modification H2 was further characterized by IR- andRaman-spectroscopy. FT-Raman and FT-IR spectra were obtained by standardtechniques as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.24 and 2.02.48. For measurement of the FT-IR andFT-Raman-spectra a Bruker Vector 22 and a Bruker RFS 100 spectrometerwere used. FT-IR spectra were base-line corrected using Bruker OPUSsoftware. FT-Raman spectra were vector normalized using the samesoftware.

An FT-IR spectrum was obtained using a KBr pellet as sample preparationtechnique. The FT-IR spectrum is depicted in FIG. 21 and the bandpositions are given below.

Crystalline modification H2 IR band positions ±2 cm⁻¹ (relativeintensity*) *“s”=strong (transmittance≦50%), “m”=medium(50%<transmittance≦70%), “w”=weak (transmittance>70%)

3481 cm⁻¹ (s), 3433 cm⁻¹ (s), 3067 cm⁻¹ (w), 2919 cm⁻¹ (w), 2618 cm⁻¹(m), 2520 cm⁻¹ (m), 2229 cm⁻¹ (m), 1669 cm⁻¹ (s), 1653 cm⁻¹ (s), 1591cm⁻¹ (s), 1577 cm⁻¹ (s), 1551 cm⁻¹ (m), 1435 cm⁻¹ (s), 1279 cm⁻¹ (s),1158 cm⁻¹ (m), 1070 cm⁻¹ (w), 1005 cm⁻¹ (m), 905 cm⁻¹ (m), 844 cm⁻¹ (m),810 cm⁻¹ (m), 770 cm⁻¹ (m), 683 cm⁻¹ (m)

An FT-Raman spectrum is depicted in FIG. 22 and the band positions aregiven below.

Crystalline modification H2 Raman band positions ±2 cm⁻¹ (relativeintensity*): *“s”=strong (relative Raman intensity≧0.04), “m”=medium(0.04>relative Raman intensity≧0.02), “w”=weak (relative Ramanintensity<0.02)

3075 cm⁻¹ (w), 2959 cm⁻¹ (w), 2229 cm⁻¹ (m), 1592 cm⁻¹ (s), 1578 cm⁻¹(m), 1490 cm⁻¹ (w), 1445 cm⁻¹ (w), 1434 cm⁻¹ (m), 1420 cm⁻¹ (m), 1340cm⁻¹ (m), 1325 cm⁻¹ (m), 1306 cm⁻¹ (m), 1187 cm⁻¹ (w), 1001 cm⁻¹ (m),836 cm⁻¹ (w)

Crystalline modification H2 is a crystalline monohydrate form, which isfurther characterized by the following physical properties:

-   -   Thermal behaviour of crystalline modification H2 shows no loss        of hydrate water ≦80° C. From approx. 80-150° C. dehydration        occurs with loss of crystallinity and subsequent        re-crystallisation of the anhydrous form. At approx. 230° C.        melting occurs. DSC profile (Mettler-Toledo DSC 821, 5 K/min,        nitrogen purge gas 50 mL/min) and TGA profile (Mettler-Toledo        DSC 851, 5 K/min, nitrogen purge gas 50 mL/min) are displayed in        FIGS. 23 and 24, respectively.    -   Water Vapor Sorption behavior shows small water uptake levels up        to 98% relative humidity (RH), and crystalline modification H2        can be classified as non-hygroscopic acc. to Ph. Eur. criteria.        At dry RH conditions, no loss of hydrate water is observed.        Water Vapor Sorption isotherm (25° C.) of crystalline        modification H2 is displayed in FIG. 25.    -   Thermodynamic solubility of crystalline modification H2 in 0.1 N        HCl (pH 1.0) at 37° C. was determined to be approx. 28 μg/mL.        Solubility of crystalline modification H2 in Simulated Gastric        Fluid (acc. to USP) at ambient conditions (approx. 20-25° C.)        was determined to be approx. 20 μg/mL.    -   Kinetic Solubility (after 60 minutes) of crystalline        modification H2 in 0.1 N HCl (pH 1.0) at room temperature        (approx. 20-25° C.) was determined to be approx. 0.3 μg/mL.

Assessment of thermodynamic stability compared to other hydrate forms H1and NF3 by competitive binary slurry conversion experiments in a seriesof different solvents at 25° C. and 50° C. reveals that crystallinemodification H2 is the thermodynamically stable hydrate form.

Example 12 Reproduction of Example 4 of PCT/EP2008/005508 (Manufactureof Compound “A7”)

Approx. 511 mg of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilewere dispersed in 75 mL acetone, and approx. 1.12 mL of 1 N aqueous HClsolution were added (Note: in contrast to Example 4 ofPCT/EP2008/005508, no clear solution was obtained. However, theremaining solid-state residue was removed by filtration to yield a clearsolution afterwards). The resulting clear solution was then incubatedovernight, whereupon crystals were obtained. The crystals were separatedby filtration, and dried for 1 h in a vacuum drying cabinet at 65° C.

A Powder X-Ray Diffraction pattern of compound “A7” was obtained bystandard techniques as described in the European Pharmacopeia 6^(th)Edition chapter 2.9.33, and is characterized by the following X-raypowder diffractogram (Cu—Kα₁ radiation, λ=1.5406 Å, Stoe StadiP 611 KLdiffractometer) depicted in FIG. 26.

Compound “A7” is characterized by the following XRD data:

Powder X-ray diffractogram peak list: °2θ (Cu—Kα₁ Peak No. d/Åradiation) ± 0.1° 1 8.74 10.1 2 8.23 10.7 3 7.62 11.6 4 6.78 13.0 5 6.5813.4 6 5.74 15.4 7 4.99 17.8 8 4.85 18.3 9 4.68 18.9 10 4.44 20.0 114.36 20.3 12 3.73 23.8 13 3.64 24.4 14 3.39 26.3 15 3.14 28.4

Powder X-Ray Diffraction pattern depicted in FIG. 26 and correspondingXRD data confirm that compound “A7” is crystalline modification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

The reproduction of Example 4 of PCT/EP2008/005508 (manufacture ofcompound “A7”) was repeated for a second time: approx. 511 mg of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilewere dispersed in 75 mL acetone, and approx. 1.12 mL of 1 N aqueous HClsolution were added (Note: in contrast to Example 4 ofPCT/EP2008/005508, no clear solution was obtained. However, theremaining solid-state residue was removed by filtration to yield a clearsolution afterwards). The resulting clear solution was then agitated for16 hours, whereupon crystals were obtained. The crystals were separatedby filtration, washed with acetone, and dried in a vacuum dryingcabinet.

Another Powder X-Ray Diffraction pattern of compound “A7” was obtainedby standard techniques as described in the European Pharmacopeia 6^(th)Edition chapter 2.9.33, and is characterized by the following X-raypowder diffractogram (Cu—Kα₁ radiation, λ=1.5406 Å, Stoe StadiP 611 KLdiffractometer) depicted in FIG. 27.

Compound “A7” is characterized by the following XRD data:

Powder X-ray diffractogram peak list: °2θ (Cu—Kα₁ Peak No. d/Åradiation) ± 0.1° 1 8.75 10.1 2 8.23 10.7 3 7.62 11.6 4 6.80 13.0 5 6.6013.4 6 5.75 15.4 7 4.99 17.7 8 4.86 18.2 9 4.69 18.9 10 4.44 20.0 114.37 20.3 12 3.74 23.8 13 3.64 24.4 14 3.39 26.2 15 3.14 28.4

Again, Powder X-Ray Diffraction pattern depicted in FIG. 27 andcorresponding XRD data confirm that compound “A7” is crystallinemodification H2 of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate.

Example 13

Structural and physico-chemical characterization of3-(1-{3-[5-(1-methyl-pipendin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification NF6

A Powder X-Ray Diffraction pattern of crystalline modification NF6 wasobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.9.33, and is characterized by thefollowing X-ray powder diffractogram (Cu—Kα₁ radiation, λ=1.5406 Å, StoeStadiP 611 KL diffractometer) depicted in FIG. 28.

Crystalline modification NF6 is characterized by the following XRD data:

Powder X-ray diffractogram peak list: °2θ (Cu—Kα₁ Peak No. d/Åradiation) ± 0.1° 1 17.66 5.0 2 11.07 8.0 3 10.53 8.4 4 9.35 9.4 5 8.7710.1 6 6.55 13.5 7 5.83 15.2 8 5.26 16.8 9 4.88 18.2 10 4.54 19.5 114.48 19.8 12 4.38 20.3 13 4.06 21.9 14 3.66 24.3 15 3.50 25.4 16 3.4525.8 17 3.32 26.8 18 3.27 27.2 19 3.21 27.8 20 3.12 28.6

Crystalline modification NF6 was further characterized by IR- andRaman-spectroscopy. FT-Raman and FT-IR spectra were obtained by standardtechniques as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.24 and 2.02.48. For measurement of the FT-IR andFT-Raman-spectra a Bruker Vector 22 and a Bruker RFS 100 spectrometerwere used. FT-IR spectra were base-line corrected using Bruker OPUSsoftware. FT-Raman spectra were vector normalized using the samesoftware.

An FT-IR spectrum was obtained using a KBr pellet as sample preparationtechnique. The FT-IR spectrum is depicted in FIG. 29 and the bandpositions are given below.

Crystalline modification NF6 IR band positions ±2 cm⁻¹ (relativeintensity*) *“s”=strong (transmittance≦50%), “m”=medium(50%<transmittance≦70%), “w”=weak (transmittance>70%)

2927 cm⁻¹ (w), 2671 cm⁻¹ (w), 2228 cm⁻¹ (w), 1683 cm⁻¹ (w), 1663 cm⁻¹(w), 1593 cm⁻¹ (w), 1577 cm⁻¹ (w), 1460 cm⁻¹ (w), 1432 cm⁻¹ (w), 1278cm⁻¹ (w), 1150 cm⁻¹ (w), 1052 cm⁻¹ (w), 1001 cm⁻¹ (w), 953 cm⁻¹ (w), 910cm⁻¹ (w), 839 cm⁻¹ (w), 803 cm⁻¹ (w), 762 cm⁻¹ (w)

An FT-Raman spectrum is depicted in FIG. 30 and the band positions aregiven below.

Crystalline modification NF6 Raman band positions ±2 cm⁻¹ (relativeintensity*): *“s”=strong (relative Raman intensity≧0.04), “m”=medium(0.04>relative Raman intensity≧0.02), “w”=weak (relative Ramanintensity<0.02)

3067 cm⁻¹ (m), 3056 cm⁻¹ (w), 2964 cm⁻¹ (m), 2883 cm⁻¹ (w), 2232 cm⁻¹(s), 1606 cm⁻¹ (s), 1577 cm⁻¹ (m), 1484 cm⁻¹ (m), 1451 cm⁻¹ (m), 1436cm⁻¹ (m), 1430 cm⁻¹ (m), 1408 cm⁻¹ (m), 1324 cm⁻¹ (s), 1316 cm⁻¹ (s),1278 cm⁻¹ (w), 1179 cm⁻¹ (m), 1001 cm⁻¹ (s), 861 cm⁻¹ (w), 839 cm⁻¹ (w)

Crystalline modification NF6 is a crystalline anhydrous form, which isfurther characterized by the following physical properties:

-   -   Thermal behavior shows starting melting processes at approx.        175° C., with subsequent recrystallisation at approx. 195° C.,        and melting/decomposition of the recrystallised phase >230° C. A        very small mass loss up to the melting temperature is observed.        DSC profile (Mettler-Toledo DSC821, 5 K/min, nitrogen purge gas        50 mL/min) and TGA profile (Perkin-Elmer Pyris TGA1, 5 K/min,        nitrogen purge gas 50 mL/min) are displayed in FIGS. 31 and 32,        respectively.    -   Water Vapor Sorption behavior shows a pronounced water uptake in        the initial sorption stage at 40% relative humidity (RH), with        subsequent full re-desorption from 30-0%. Upon 2^(nd) adsorption        cycle, a pronounced water uptake up to approx. 8 wt % is        observed up to 70% RH. Water Vapor Sorption isotherm (25° C.) of        crystalline modification NF6 is displayed in FIG. 33.

Thermodynamic Solubility of crystalline modification NF6 in 0.1N HCl (pH1.0) at 37° C. was determined to be >200 μg/mL

Example 14 Structural and physico-chemical characterization of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride anhydrate in its crystalline modification NF4

A Powder X-Ray Diffraction pattern of crystalline modification NF4 wasobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.9.33, and is characterized by thefollowing X-ray powder diffractogram (Cu—Kα₁ radiation, λ=1.5406 Å, StoeStadiP 611 KL diffractometer) depicted in FIG. 34.

Crystalline modification NF4 is characterized by the following XRD data:

Powder X-ray diffractogram peak list: °2θ (Cu—Kα₁ Peak No. d/Åradiation) ± 0.1° 1 14.61 6.0 2 8.92 9.9 3 6.45 13.7 4 6.29 14.1 5 5.6315.7 6 5.53 16.0 7 5.28 16.8 8 4.86 18.2 9 4.19 21.2 10 4.11 21.6 114.04 22.0 12 3.94 22.6 13 3.89 22.8 14 3.76 23.6 15 3.60 24.7 16 3.5625.0 17 3.49 25.5 18 3.37 26.5 19 3.32 26.8 20 3.22 27.7

Example 15

Structural and physico-chemical characterization of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in its crystalline modification NF2

A Powder X-Ray Diffraction pattern of crystalline modification NF2 wasobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.9.33, and is characterized by thefollowing X-ray powder diffractogram (Cu—Kα₁ radiation, λ=1.5406 Å, StoeStadiP 611 KL diffractometer) depicted in FIG. 35.

Crystalline modification NF2 is characterized by the following XRD data:

Powder X-ray diffractogram peak list: °2θ (Cu—Kα₁ Peak No. d/Åradiation) ± 0.1° 1 16.84 5.2 2 8.41 10.5 3 8.14 10.9 4 5.70 15.5 5 5.5915.8 6 4.87 18.2 7 4.19 21.2 8 4.00 22.2 9 3.91 22.7 10 3.78 23.5 113.73 23.8 12 3.63 24.5 13 3.52 25.3 14 3.49 25.5 15 3.36 26.5 16 3.3326.7 17 3.23 27.6 18 3.19 28.0 19 3.15 28.3 20 3.12 28.6

Crystalline modification NF2 is a crystalline hydrate form, which isfurther characterized by the following physical properties:

-   -   Thermal behavior shows a strong and broad endothermic event in        the DSC, going along with pronounced weight loss-9-10 wt % in        the TGA, at temperatures ˜30-50° C. Further heating reveals        melting at approx. 135° C., with immediate recrystallisation at        approx. 155° C., and subsequent melting/decomposition of the        recrystallised phase >230° C. Up to approx. 150° C., further        weight loss is observed upon heating in the TGA scan. DSC        profile (Mettler-Toledo DSC821, 5 K/min, nitrogen purge gas 50        mL/min) and TGA profile (Perkin-Elmer Pyris TGA1, 5 K/min,        nitrogen purge gas 50 mL/min) are displayed in FIGS. 36 and 37,        respectively.    -   Water Vapor Sorption behavior shows a pronounced weight loss in        the initial 40% RH sorption stage of ˜10 wt %, followed by        reversible desorption/adsorption processes in the relative        humidity (RH) range 40-0-70%. A strongly hygroscopic behaviour        is observed at relative humidity (RH) levels >70%. Water Vapor        Sorption isotherm (25° C.) of crystalline modification NF6 is        displayed in FIG. 38.

1-19. (canceled)
 20. A method for the treatment of a physiological orpathophysiological condition, which is caused, mediated, or propagatedby Met-kinase, said method comprising administering to a patient aneffective amount of a compound selected from the following compounds:(a) a crystalline form of a hydrochloride solvate of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile,excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate in the form of a polymorph characterized bythe following XRD data: °2θ (Cu—Kα₁ Peak No. d/Å radiation) (h, k, l) 18.71 10.1 (1, 0, 0) 2 8.22 10.8 (−1, 1, 1) 3 7.59 11.6 (1, 2, 0) 4 6.7813.0 (0, 3, 1) 5 6.58 13.5 (−1, 3, 1) 6 5.73 15.4 (−1, 4, 1) 7 4.98 17.8(−1, 1, 2) 8 4.84 18.3 (−2, 1, 1) 9 4.68 19.0 (−2, 2, 1) 10 4.43 20.0(−2, 3, 1) 11 4.35 20.4 (2, 0, 0) 12 3.73 23.9 (−2, 4, 2) 13 3.64 24.5(0, 5, 2) 14 3.39 26.3 (0, 6, 2) 15 3.13 28.5 (−3, 2, 2)

or (b) the hydrochloride anhydrate of the compound3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile.21. A method according to claim 20, wherein said physiological and/orpathophysiological condition is cancer.
 22. (canceled)
 23. The methodaccording to claim 20 wherein said compound the medicament is appliedbefore, during, or after treatment with at least one additionalpharmacologically active substance. 24-34. (canceled)
 35. A methodaccording to claim 20, wherein said physiological and/orpathophysiological condition is a tumor selected from malignant tumors,benign tumors, solid tumors, sarcomas, carcinomas, Ewing sarcomas,Kaposi sarcomas, brain tumors, gliomas, glioblastomas, neuroblastomas,prostate carcinomas, connective tissue tumors, soft tissue sarcomas,pancreas tumors, liver tumors, head tumors, neck tumors, laryngealcancer, osteosarcomas, retinoblastomas, lung adenocarcinoma, small celllung carcinoma, bronchial carcinomas, mamma carcinomas, colorectaltumors, colon carcinomas, rectum carcinomas, gynecological tumors,ovarian tumors, cervix carcinomas, corpus carcinomas, endometrialcarcinomas, epithelial tumor, squamous epithelial carcinoma, basaliomas,spinaliomas, melanomas, and intraocular melanomas.
 36. A methodaccording to claim 21, wherein said cancer is stomach cancer, kidneycancer, prostate cancer, laryngeal cancer, esophageal cancer, thyroidcancer, testicular cancer, lung cancer, breast cancer, intestinalcancer, uterine cancer, cervical cancer, cervix carcinomas, cancer ofbody of uterus, urinary bladder cancer, urogenital tract cancer, bladdercancer, skin cancer, monocyte leukemia, chronic leukemias, chronicmyelotic leukemia, chronic lymphatic leukemia, acute leukemias, acutemyelotic leukemia, acute lymphatic leukemia or lymphomas.
 37. The methodaccording to claim 20, wherein said compound is a crystalline form of ahydrochloride solvate of3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile,excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate in the form of a polymorph characterized bythe following XRD data: °2θ (Cu—Kα₁ Peak No. d/Å radiation) + 0.1° (h,k, l) 1 8.71 10.1 (1, 0, 0) 2 8.22 10.8 (−1, 1, 1) 3 7.59 11.6 (1, 2, 0)4 6.78 13.0 (0, 3, 1) 5 6.58 13.5 (−1, 3, 1) 6 5.73 15.4 (−1, 4, 1) 74.98 17.8 (−1, 1, 2) 8 4.84 18.3 (−2, 1, 1) 9 4.68 19.0 (−2, 2, 1) 104.43 20.0 (−2, 3, 1) 11 4.35 20.4 (2, 0, 0) 12 3.73 23.9 (−2, 4, 2) 133.64 24.5 (0, 5, 2) 14 3.39 26.3 (0, 6, 2) 15 3.13 28.5 (−3, 2, 2).


38. The method according to claim 20, wherein said compound is thehydrochloride anhydrate of the compound3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile.39. The method according to claim 38, wherein said compound is in theform of a polymorph characterized by XRD peaks comprising 4.4°, 15.9°and 22.7° (in °2θ using Cu—Kα₁ radiation, ±0.1°).
 40. The methodaccording to claim 38, wherein said compound is characterized by thefollowing XRD data: °2θ (Cu—Kα₁ Peak No. d/Å radiation) ± 0.1° 1 20.084.4 2 8.55 10.3 3 7.43 11.9 4 5.70 15.5 5 5.56 15.9 6 4.99 17.8 7 4.8618.2 8 4.74 18.7 9 4.55 19.5 10 4.46 19.9 11 4.27 20.8 12 4.10 21.6 133.91 22.7 14 3.82 23.3 15 3.65 24.3.


41. The method according to claim 37, wherein said compound is3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate, excluding3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride monohydrate crystalline in the form of said polymorph. 42.The method according to claim 41, wherein said compound is in the formof a polymorph characterized by XRD peaks comprising 5.9°, 16.0° and23.4° (in °2θ using Cu—Kα₁ radiation, ±0.1°).
 43. The method accordingto claim 41, wherein said compound is in the form of a polymorphcharacterized by the following XRD data: °2θ (Cu—Kα₁ Peak No. d/Åradiation) ± 0.1° 1 14.88 5.9 2 9.99 8.8 3 7.83 11.3 4 7.25 12.2 5 6.1014.5 6 5.84 15.2 7 5.52 16.0 8 5.38 16.5 9 4.92 18.0 10 4.12 21.6 113.80 23.4 12 3.57 24.9 13 3.49 25.5 14 3.30 27.0 15 2.95 30.3.


44. The method according to claim 41, wherein said compound is in theform of a polymorph characterized by XRD peaks comprising 9.9°, 15.7°and 24.1 (in °2θ using Cu—Kα₁ radiation, ±0.1°).
 45. The methodaccording to claim 41, wherein said compound is in the form of apolymorph characterized by the following XRD data: °2θ (Cu—Kα₁ Peak No.d/Å radiation) ± 0.1° 1 14.83 6.0 2 8.96 9.9 3 6.92 12.8 4 5.62 15.7 55.44 16.3 6 5.26 16.9 7 4.38 20.3 8 4.32 20.6 9 3.79 23.5 10 3.69 24.111 3.59 24.8 12 3.55 25.1 13 3.45 25.8 14 3.35 26.6 15 3.22 27.7.


46. The method according to claim 38, wherein said compound is in theform of a polymorph characterized by XRD peaks comprising 16.8°, 18.2°and 25.8° (in °2θ using Cu—Kα₁ radiation, ±0.1°).
 47. The compoundaccording to claim 38, wherein said compound is in the form of apolymorph characterized by the following XRD data: °2θ (Cu—Kα₁ Peak No.d/Å radiation) ± 0.1° 1 17.66 5.0 2 11.07 8.0 3 10.53 8.4 4 9.35 9.4 58.77 10.1 6 6.55 13.5 7 5.83 15.2 8 5.26 16.8 9 4.88 18.2 10 4.54 19.511 4.48 19.8 12 4.38 20.3 13 4.06 21.9 14 3.66 24.3 15 3.50 25.4 16 3.4525.8 17 3.32 26.8 18 3.27 27.2 19 3.21 27.8 20 3.12 28.6.


48. The method according to claim 38, wherein said compound is in theform of a polymorph characterized by XRD peaks comprising 6.0°, 15.7°and 24.7° (in °2θ using Cu—Kα₁ radiation, ±0.1°).
 49. The methodaccording to claim 38, wherein said compound is in the form of apolymorph characterized by the following XRD data: °2θ (Cu—Kα₁ Peak No.d/Å radiation) ± 0.1° 1 14.61 6.0 2 8.92 9.9 3 6.45 13.7 4 6.29 14.1 55.63 15.7 6 5.53 16.0 7 5.26 16.8 8 4.86 18.2 9 4.19 21.2 10 4.11 21.611 4.04 22.0 12 3.94 22.6 13 3.89 22.8 14 3.76 23.6 15 3.60 24.7 16 3.5625.0 17 3.49 25.5 18 3.37 26.5 19 3.32 26.8 20 3.22 27.7.


50. The method according to claim 41, wherein said compound is in theform of a polymorph characterized by XRD peaks comprising 5.2°, 23.8°and 24.5° (in °2θ using Cu—Kα₁ radiation, ±0.1°).
 51. The methodaccording to claim 41, wherein said compound is in the form of apolymorph characterized by the following XRD data: °2θ (Cu—Kα₁ Peak No.d/Å radiation) ± 0.1° 1 16.84 5.2 2 8.41 10.5 3 8.14 10.9 4 5.70 15.5 55.59 15.8 6 4.87 18.2 7 4.19 21.2 8 4.00 22.2 9 3.91 22.7 10 3.78 23.511 3.73 23.8 12 3.63 24.5 13 3.52 25.3 14 3.49 25.5 15 3.36 26.5 16 3.3326.7 17 3.23 27.6 18 3.19 28.0 19 3.15 28.3 20 3.12 28.6.


52. The method according to claim 37, wherein said compound is a solvateof water, methanol, ethanol, propan-1-ol, propan-2-ol, ethyl acetate,acetonitrile, acetone, butanone, tetrahydrofuran, chloroform, n-heptane,or toluene.
 53. The method according to claim 52, wherein said compoundis a solvate of water, acetone, tetrahydrofuran, methanol, ethylacetate, or n-heptane.